Cardiopulmonary Exercise Test to Detect Cardiac Dysfunction from Pulmonary Vascular Disease

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Yang, Demosthenes G. Papamatheakis, W. Cameron McGuire, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3411609/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Mar, 2024 Read the published version in Respiratory Research → Version 1 posted 8 You are reading this latest preprint version Abstract Background Cardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease. Methods We reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O 2 ·pulse AT /O 2 ·pulse rest with RHC-determined SV AT /SV rest . We evaluated the sensitivity and specificity of O 2 ·pulse AT /O 2 ·pulse rest to detect SV AT /SV rest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRV peak ) with SV AT /SV rest . Results From July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O 2 ·pulse and SV at rest and at AT. O 2 ·pulse AT /O 2 ·pulse rest correlated highly with SV AT /SV rest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRV peak did not (r = -0.09, 95% CI -0.47, 0.33; p < 0.69). The AUROC to detect SV AT /SV rest below the LLN was significantly higher for O 2 ·pulse AT /O 2 ·pulse rest (0.92, SE 0.04; p = 0.0002) than for TRV peak (0.69, SE 0.10; p = 0.12). O 2 ·pulse AT /O 2 ·pulse rest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SV AT /SV rest . Conclusions CPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O 2 ·pulse AT /O 2 ·pulse rest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism. cardiopulmonary exercise test (CPET) echocardiography pulmonary embolism stroke volume augmentation pulmonary vascular disease Figures Figure 1 Figure 2 Figure 3 Introduction Cardiopulmonary exercise testing (CPET) had been proposed as a noninvasive method to detect pulmonary vascular disease among patients with dyspnea and exercise intolerance after acute pulmonary embolism (PE). 1,2 Pulmonary vascular disease-associated cardiac limitation is manifested by inadequate stroke volume (SV) augmentation in response to exercise. 3,4 CPET has disclosed evidence of inadequate SV augmentation in over half of patients with dyspnea after PE. 5 However, CPET findings suggestive of pathologically decreased SV augmentation have never been validated against the gold standard of direct measurement by right heart catheterization (RHC) in patients with pulmonary vascular disease. The “direct Fick method” of measuring SV by RHC requires simultaneous determination of oxygen consumption rate (VO 2 ), mixed venous O 2 content, arterial O 2 content and heart rate. The procedure, though highly accurate, is too invasive and too expensive to evaluate stroke volume augmentation among the vast numbers of patients with post-PE dyspnea. SV, however, is related to VO 2 /heart rate (O 2 ·pulse) and the difference between arterial and mixed venous oxygen content (C a−v O 2 ) according to the equation SV = O 2 ·pulse/C a−v O 2 . It has been shown among patients with pulmonary vascular disease that the trajectory of O 2 ·pulse increase during exercise does indeed reflect the pattern expected of SV increase. 6 Furthermore, since (C a−v O 2 ) increases predictably between rest and anaerobic threshold (AT), SV augmentation between rest and AT (SV AT /SV rest ) is reflected on CPET by the relative increase in O 2 ·pulse between AT and rest (O 2 ·pulse AT /O 2 ·pulse rest ): SV AT /SV rest = (O 2 ·pulse AT /O 2 ·pulse rest )/(C a−v O 2_AT /C a−v O 2_rest ). 7 We retrospectively reviewed our clinical experience with combined CPET and RHC examinations to determine whether, in patients with suspected pulmonary vascular disease, O 2 ·pulse AT /O 2 ·pulse rest , measured noninvasively by CPET predicts abnormally low SV AT /SV rest , measured invasively by RHC. Methods Subjects We reviewed the results of simultaneous RHC and CPET among consecutive patients suspected of having pulmonary vascular disease who were referred to the University of California, San Diego from January 2018 through February 2023. RHC-CPET was performed based on the clinical judgement of the pulmonary vascular specialist. Among patients with more than one study, we evaluated only the first study. Inclusion criteria were: (1) measurement, at rest, of heart rate (HR rest ), cardiac output (Q rest ) by the direct Fick method and O 2 ·pulse rest ; (2) measurement, at an independently determined AT point, of O 2 ·pulse AT ; and (3) measurement, when VO 2 was within 20% of the VO 2 at AT, of HR AT and Q AT . There were no exclusion criteria. The University of California, San Diego Institutional Review Board approved the study (IRB #171888). Right heart catheterization and SVA AT RHC was performed at rest and during exercise as previously described. 8 A radial artery catheter and a pulmonary artery catheter were inserted in the cardiac catheterization laboratory while patients were in the supine position. Right atrial, right ventricular, pulmonary artery, and pulmonary artery occlusion pressure were measured in succession. Once a stable respiratory quotient was observed with the patient at rest, heart rate was recorded, and cardiac output was determined with the direct Fick method from the measured VO2 and simultaneous radial artery and pulmonary artery blood gases. The subjects then performed incrementally increased exercise on a supine cycle ergometer (Medical Positioning, Inc.), as described below. Heart rate and cardiac output measurements were repeated in a similar fashion during exercise at point near anerobic threshold (as determined in real-time by a change in the slope VCO2 versus VCO2) and again near peak exertion. Hemodynamic data were collected without knowledge of the CPET results. SV AT /SV rest was calculated as SV AT /SV rest = (Q AT / HR AT ) / (Q rest / HR rest ), where Q AT and Q rest represent cardiac output at anaerobic threshold and at rest, respectively, and HR AT and HR rest represent heart rate at anaerobic threshold and at rest, respectively. We pre-specified the lower limit of normal for SV AT /SV rest based right heart catheterization data from healthy volunteers, in whom stroke volume increased by 38.8% (SD 5.2%) between rest and AT. 7 We arbitrarily selected the mean minus two times the standard deviation from that experiment (128%) as the SV AT /SV rest lower limit of normal (LLN) for the current study. Cardiopulmonary exercise test determination of O 2 ·pulse rest and O2·pulse AT Simultaneously with the RHC, we performed incremental symptom-limited CPET with the patients on a recumbent bicycle, using a stepwise exercise protocol to produce a uniform increase in work rate and metabolic energy expenditure per incremental step. O 2 ·pulse rest was determined during steady state rest with a V-Max metabolic cart (CareFusion, San Diego, CA) or a Ultima Cardio2 metabolic cart (MGC Diagnostics, St Paul, MN) from VO 2 , measured through breath-by-breath analysis of inspired and expired gases and heart rate, measured by continuous electrocardiography (Fig. 1 ). Anaerobic threshold was determined by the V-slope method by a board-certified pulmonologist (TM) without knowledge of the RHC results. O 2 ·pulse AT was determined retrospectively during the 20-second interval containing the anaerobic threshold point (Fig. 1 ). Echocardiography For comparison, peak tricuspid regurgitation velocity (TRV peak ) and other signs of pulmonary vascular disease 9 were recorded from echocardiograms that had been performed within six months of the combined CPET-RHC studies. In addition, the echocardiographic results were categorized as high- or intermediate-risk vs low-risk, according to the recommendations of the European Society of Cardiology and the European Respiratory Society (ESC/ERS) Task Force for the Diagnosis and Management of Acute Pulmonary Embolism 10 and the ESC/ERS Task Force for the Diagnosis and Treatment of Pulmonary Hypertension. 9 Statistical analysis Continuous variables are presented as mean (+/- standard deviation) or median and interquartile range [IQR]. Categorical variables are presented as number (%). Pearson correlation was used to compare O 2 ·pulse AT /O 2 ·pulse rest to SV AT /SV rest and to compare TRV peak to SV AT /SV rest . O 2 ·pulse AT /O 2 ·pulse rest and TRV peak were also linearly regressed on SV AT /SV rest . Receiver operating characteristic curves were plotted to compare the sensitivities and specificities of O 2 ·pulse AT /O 2 ·pulse rest and TRV peak for detecting SV AT /SV rest below the lower limit of normal (LLN = 1.28). 7 We defined 90% as an acceptable sensitivity for a screening test to detect SV AT /SV rest below the LLN. Statistical calculations were performed with Prism version 9 (GraphPad Software, San Diego CA). Results Study population During the study period, 83 simultaneous RHC and CPET tests were performed. Forty-seven tests were not included because blood was not sampled from the systemic artery (n=8) or pulmonary artery (n=1) for direct Fick cardiac output measurement; anaerobic threshold was not reached or was indeterminate (n=8); or cardiac output was not measured during exercise while the VO 2 was within 20% of VO 2 at anaerobic threshold (n=30). Thirty-six tests met the inclusion criteria and were included in the analysis (Fig. 2). The demographics and hemodynamics of the excluded patients were not different from the included patients (Table e1). Included patients were 56.5 [40.25, 66] years of age and had body mass index (BMI) of 28 [24.1, 32.5] kg/m 2 (Table 1). There were 11 (30.6%) men and 25 (69.4%) women. 12 patients (33.3%) had co-existing cardiopulmonary comorbidities. All patients exercised to the point of volitional exhaustion without adverse effects. The distribution of hemodynamic measurements and CPET parameters are illustrated in Tables 2 and 3, respectively. Relationship between O 2 ·pulse AT /O 2 ·pulse rest and SVA AT Figure 3A illustrates a statistically significant linear correlation between O 2 ·pulse AT /O 2 ·pulse rest and SV AT /SV rest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001). Linear regression yielded a slope of 0.51 (95% CI 0.48, 0.55) between SV AT /SV rest and O 2 ·pulse AT /O 2 ·pulse rest . The LLN for SV AT /SV rest (1.28) corresponded to O 2 ·pulse AT /O 2 ·pulse rest of 2.5 (95% CI 2.3, 2.7). In contrast, Figure 3C shows no significant correlation between TRV peak and SV AT /SV rest (r = -0.09, 95% CI -0.47, 0.33; p < 0.69). The area under the receiver operating characteristic curve (AUROC) of O 2 ·pulse AT /O 2 ·pulse rest for detecting SV AT /SV rest below the LLN (Fig 3B) was 0.92 (SE 0.04, p = 0.0002). The AUROC 95% CI was 0.832 to 1.00. O 2 ·pulse AT /O 2 ·pulse rest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%). O 2 ·pulse AT /O 2 ·pulse rest of less than 2.2 was only 74 % sensitive (95% CI 55.3%, 86.8%) but 100% specific (95% CI 70.1%, 100%). The AUROC of TRV peak to detect SV AT /SV rest below the LLN (Fig. 3D) was 0.69 (SE 0.10, p = 0.12). The AUROC 95% CI was 0.495 to 0.889, which includes the nondiscriminatory value of 0.5. No value of TRV peak had a sensitivity of 90% or higher. Echocardiography meeting the ESC/ERS criteria 10 for intermediate- or high-risk (TRV peak >2.8 and/or presence of two other pulmonary hypertension signs 9 ) was only 23.0% sensitive (95% CI 11.0%, 42.0%) but 100% specific (95% CI 64.6%, 100%) for detecting SV AT /SV rest below the LLN. Discussion We validated the accuracy of O 2 ·pulse AT /O 2 ·pulse rest to predict SV AT /SV rest in a consecutive series of patients receiving combined CPET and RHC for the clinical evaluation of dyspnea potentially related to pulmonary vascular disease. We derived a cutoff of 2.6 for O 2 ·pulse AT /O 2 ·pulse rest to predict SV AT /SV rest less than the LLN. We observed a highly significant linear relationship between O 2 ·pulse AT /O 2 ·pulse rest and SV AT /SV rest , with a slope that corresponds with previous CPET-RHC comparisons among healthy subjects and among patients with various severities of heart failure. 7,11–15 . Although O 2 ·pulse AT /O 2 ·pulse rest enables merely an estimate of the RHC measurement of SV AT /SV rest , the correlation between the two is comparable to or even superior to the correlation between different invasive methods of measuring stroke volume by RHC. 16–19 SV augmentation is an important adaptation to exercise that helps increase cardiac output and maintain organ perfusion during increased oxygen utilization. 12 Increased venous pressure during exercise enhances right ventricular end-diastolic volume 20 and normally improves contractility. 21 SV rises incrementally as exercise proceeds and reaches a plateau near AT. 7,12,22–24 In healthy persons, there is an approximately 40% increase in SV by the time AT is reached. 7 The advantage to considering SV AT /SV rest , rather than SV AT alone, is that the ratio controls for demographic factors (body size, age, sex, etc.) that typically influence SV. Pulmonary vascular disease leads to elevated right ventricular end-diastolic volume and impaired contractility at rest, which impedes the normal adaptation to exercise. 21 As a result, SV augmentation is markedly decreased 3,4 Residual pulmonary vascular obstruction limits SV augmentation, increases pulmonary artery resistance and compromises right ventricular function. 25,26 Since SV augmentation substantially improves among CTEPH patients after pulmonary artery thromboendarterectomy, it is reasonable to attribute the defect to pulmonary vascular obstruction itself. 4 Furthermore, insufficient SVA in response to exercise predicts mortality from pulmonary hypertension more accurately than any other exercise parameter and enhances the accuracy of mortality prediction above the six minute walking distance alone. 27 Although CTEPH is present in only a small fraction of patients with dyspnea after PE, 28 less severe pulmonary vascular disease causes respiratory symptoms, 29 hypoxemia, 30–32 gas exchange deficits 31,33,34 and exercise intolerance. 35 Residual pulmonary vascular obstruction is associated with the risk of progression to CTEPH. 36 In our previous series of CPET for patients with long-term dyspnea after acute pulmonary embolism, low O 2 ·pulse AT /O 2 ·pulse rest corresponded to residual pulmonary artery obstruction. 5 Among symptomatic post-pulmonary embolism patients, low O 2 ·pulse AT /O 2 ·pulse rest measured noninvasively during CPET suggests inadequate SV augmentation because of residual pulmonary vascular occlusion. 5 Validation that O 2 ·pulse AT /O 2 ·pulse rest accurately reflects SV augmentation enables CPET to be an informative and practical noninvasive tool to help distinguish between pulmonary vascular disease and deconditioning or anxiety (in the absence of physiological defects) among the large number of patients with dyspnea after pulmonary embolism. 1 Our results compliment the results of Held et al. and of McCabe et al., who disclosed abnormal CPET findings in a majority of patients in whom CTED or CTEPH had been confirmed by RHC. 37,38 As was the case in our study, echocardiography (including TRV peak ) was unable to detect pulmonary vascular disease in 31% of CTEPH patients. 37 The insensitivity likely refects the fact that echocardiography is routinely performed at rest, which may not reflect defects that are manifested only during exercise. However, we recognize that echocardiography typically preceded RHC-CPET, at times by several months. It is possible that the difference between echocardiographic and CPET results were influenced by disease progression among some patients. Notably, CPET data from CTED and CTEPH patients reported by Held et al. and McCabe et al reflected ventilatory inefficiency, presumably based on ventilation/perfusion mismatching. 37,38 We observed similar ventilatory inefficiency in our patients, which we are investigating in a separate study. The current study focuses on the ability of O 2 ·pulse AT /O 2 ·pulse rest , to reflect stroke volume augmentation itself. However, we anticipate that both factors are likely implicated in pulmonary vascular disease after acute PE. 5,39 Since acute pulmonary embolism occurs in about 63/100,000 persons per year, 40 up to half of whom report chronic dyspnea, 41–43 the method we validated could detect SV augmentation limitation due to pulmonary vascular disease in a large number of at-risk patients. 28 It is more practical than RHC and more sensitive than echocardiography. Since our patients ranged from normal to very poor cardiopulmonary reserve during exercise, our results suggest that O 2 ·pulse AT /O 2 ·pulse rest would reflect SV augmentation across a wide spectrum of dysfunction. Besides acute pulmonary embolism, there are numerous risk factors associated with pulmonary vascular disease, including scleroderma and other connective tissue diseases. In these at-risk patients, symptoms begin with dyspnea on exertion, but pulmonary hypertension may not be present at rest. Non-invasive CPET to screen for decreased exercise-related stroke volume augmentation by detecting impaired O 2 ·pulse AT /O 2 ·pulse rest has the potential to identify these patients as well, earlier in their disease course. ESC/ERS guidelines recommend transthoracic echocardiography as an initial test to evaluate dyspnea on exertion after pulmonary embolism. 10 However, while TTE can be useful as a screen for chronic thromboembolic pulmonary hypertension (CTEPH), it may not be the best approach for evaluating patients who are limited by persistent perfusion defects that cause exercise-induced pulmonary hypertension. Our present research has shown that tricuspid regurgitant velocity peak is less sensitive than non-invasively measured O2·pulse AT /O2·pulse rest in detecting directly measured SVA AT below the lower limit of normal. Therefore, we recommend non-invasive cardiopulmonary exercise testing (CPET) as the first step in evaluating dyspnea after PE. Like other studies of CPET and RHC for pulmonary vascular disease, 37,38 our study is limited by its relatively small size and its retrospective nature. In addition, because O 2 ·pulse AT /O 2 ·pulse rest , reflects SV augmentation at AT, our study included only RHC tests that measured both SV rest and SV near AT. Estimation of SV augmentation from O 2 ·pulse ratios at other times would have been erroneous due to changes in oxygen extraction and heart rate during exercise above AT. 7,12,22–24 Nevertheless, with careful attention to technique, SV AT /SV rest could serve as a standard by which to evaluate SV augmentation during exercise. A limitation of our study is that we selected the LLN for SV AT /SV rest based on RHC-CPET studies performed on young, healthy subjects during upright cycling. Supine position increases venous return at rest and may lower the relative increase in diastolic volume during exercise that contributes to the SV response. 20 Further studies are needed to determine if the predicted and LLN for SV AT /SV rest should be different between upright and recumbent CPETs. Chronotropic incompetence may confound the clinical implication of stroke volume augmentation, since slow heart rates during exercise would allow more time for diastolic filling and potentially dampen the effect of cardiac dysfunction on stroke volume during exercise. However, it is unlikely that chronotropic incompetence played a substantial role in the current study, since heart rates were similar between subjects with normal SVA (110.3 +/- 19.5) and those with low SVA (107.2 +/- 17.4). The CPET-based estimation of SV AT /SV rest that we validated during right heart catheterization may be useful as a stand-alone test in other settings. For example, the method may be used for the noninvasive screening of ambulatory patients with a variety of cardiac and pulmonary disorders for exercise-related heart dysfunction. The method would help quantify cardiac adaptation to exercise in patients with known or suspected heart failure. We speculate that deficient stroke volume augmentation from various types of heart failure (right side or left side, systolic or diastolic) will have similar increases in C a−v O 2 between rest and AT and therefore similar effects of SV AT /SV rest on O2·pulse AT /O2·pulse rest . 7 However, we would not expect O2·pulse AT /O2·pulse rest to reflect SV AT /SV rest accurately among patients with myopathies that cause poor O2 extraction (e.g. mitochondrial enzyme defects), since the C a−v O 2 might not change in a predictable fashion at AT. Although the current study did not include such patients, it is possible that myopathies could be differentiated from stroke volume augmentation defects by differences in O2·pulse trajectories subsequent to AT. Degani-Costa et al. reported flattening of the O2·pulse trajectory (and upward deflection of the heart rate vs VO2 plot) during the later portions of exercise among subjects with pulmonary hypertension but not among those with mitochondrial myopathies. 6 We hope that our results will open a line of investigation about the role of this technique in the management of patients at risk of right ventricular dysfunction from pulmonary vascular disease. The technique may be particularly helpful in patients in whom dysfunction occurs during exercise but is not apparent at rest. Also, because SV AT /SV rest reflects overall cardiac adaptation to exercise, it is a potential predictor of poor outcomes that may supplement the roles of peak VO 2 , VO 2 at AT and V E /VCO 2 . Future research would be needed to ascertain the clinical utility of using O2·pulse AT /O2·pulse rest to evaluate patients with dyspnea of unknown origin. Summary We validated the accuracy of O 2 ·pulse AT /O 2 ·pulse rest , measured noninvasively by CPET, compared to invasive measurement of SV AT /SV rest during RHC. We derived a cutoff value of 2.6, which should be validated in future studies. Our results suggest that CPET can be used to evaluate SV augmentation in symptomatic patients at risk for pulmonary vascular disease, such as those with dyspnea after acute pulmonary embolism, to detect early compromise of the right ventricle. Abbreviations AT: anaerobic threshold; CPET: cardiopulmonary exercise test; HR AT : heart rate at anaerobic threshold; HR rest : heart rate at rest; Q AT : cardiac output at anaerobic threshold; Q rest : cardiac output at rest; RHC: right heart catheterization; SVA: stroke volume augmentation; SVA AT : stroke volume augmentation at anaerobic threshold measured by RHC; O 2 ·pulse : oxygen consumption rate divided by heart rate; O 2 ·pulse rest : O 2 ·pulse at rest; O 2 ·pulse AT : O 2 ·pulse at anaerobic threshold. Declarations Ethical Approval The University of California, San Diego Institutional Review Board approved the study (IRB #171888). Funding There was no external funding for this study. Availability of data and materials Deidentified data relevant to this study is available upon request to the corresponding author. Summary of conflict-of-interest statements: The authors report no conflicts of interest and no financial support relevant to this work. Author contribution statement: TAM and TMF contributed equally to the conception, design and execution of the research. Material preparation and data collection performed by JZY, TMF, DGP, MA, and WCM. Data analysis performed by TAM and MA. All authors contributed to writing, editing, and approved the manuscript. Acknowledgements: The authors thank, Brenda G. Money, Alicia E. Salcido, Sandee Lombardi and Cynthia Rodriguez for their performance of the technical aspects of the invasive CPETs and their expertise in processing the CPET data. We thank Khadizhat Dakaeva for her careful attention to detail in organizing the data for publication. The authors also thank Drs. William Stringer and Atul Malhotra for critical review of the manuscript and helpful comments prior to submission. References Morris TA, Fernandes TM, Channick R. How we do it: evaluation of dyspnea and exercise intolerance after acute pulmonary embolism. Chest. Farmakis IT, Valerio L, Barco S, et al. 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Klok FA, Cohn DM, Middeldorp S, et al. Quality of life after pulmonary embolism: validation of the PEmb-QoL Questionnaire. J Thromb Haemost. 2010;8(3):523-532. Klok FA, Tijmensen JE, Haeck ML, van Kralingen KW, Huisman MV. Persistent dyspnea complaints at long-term follow-up after an episode of acute pulmonary embolism: results of a questionnaire. Eur J Intern Med. 2008;19(8):625-629. Kahn SR, Hirsch AM, Akaberi A, et al. Functional and Exercise Limitations After a First Episode of Pulmonary Embolism: Results of the ELOPE Prospective Cohort Study. Chest. 2017;151(5):1058-1068. Tables Table1: Patient Characteristics (n=36) Data are presented as median [interquartile range] or count (percent) unless otherwise indicated. Patient Characteristics mn1 Included Age, years, median [IQR] 56.5 [40.25, 66] Male 11 (30.6) BMI, kg/m 2 28 [24.1, 32.5] Final Diagnosis Pulmonary Arterial Hypertension 8 (22.2) Lung disease 1 (2.8) Left Ventricular failure 5 (13.9) CTED/CTEPH 11 (30.6) Other 11 (30.6) History of Pulmonary embolism 18 (50.0) Coexisting cardiovascular disease 12 (33.3) Coexisting cardiovascular disease type Arrhythmias 0 (0.0) Coronary artery disease 2 (16.7) Hypertension 10 (83.3) Coexisting lung disease 12 (33.3) Coexisting lung disease type Asthma 4 (36.4) Diffuse parenchymal lung disease 3 (27.3) Obstructive sleep apnea 4 (36.4) BMI, body mass index. CTED, chronic thromboembolic disease. CTEPH, chronic thromboembolic pulmonary hypertension. Table 2: Hemodynamic Parameters at rest, anerobic threshold and peak exercise. Data are presented as median [interquartile range (IQR)] unless otherwise indicated. *Cardiac output was calculated by the direct Fick method. Rest Anerobic threshold Peak exercise mean arterial blood pressure, mmHg 100.5 [92, 108] 118.5 [112, 126] 128 [116, 133] mean PAP, mmHg 19 [15, 23] 32 [22.8, 34.8] 38 [30.5, 42.5] PAOP, mmHg 12 [10, 14] 18 [15.3, 20] 22 [18, 26] PVR, Wood Units 1.1 [0.5, 2.0] 1.068 [0.69, 1.67] 0.95 [0.7, 1.5] Cardiac output, L/min 6 [5, 8] 10.2 [9.0, 13.4] 13.2 [11.3, 15.9] Cardiac index, L/min/m2 3 [3, 4] 5.9 [4.4, 7.1] 6.8 [6.1, 7.9] Stroke volume, ml/beat 91.4 [65.4, 122.7] 96.2 [85.7, 124.8] 98.1 [84.7, 120.8] PaO 2 , mmHg 86 [78, 97] 79 [72, 95.5] 79 [72.5, 91.3] PaCO 2 , mmHg 38 [34, 40] 38 [35.3, 41.5] 36 [33, 40] PvO 2 , mmHg 39 [36, 43] 30.5 [27.2, 33] 28 [24, 30] Arterial saturation, % 98 [97, 99] 97.4 [95.4, 98.6] 97.6 [95.2, 98.6] PA saturation, % 76 [71, 79] 56.8 [50.1, 59.1] 46.7 [38.9, 51.3] Heart Rate, BPM 75 [65, 81] 109 [96.5,116] 139.5 [115.2, 147.8] PAP, pulmonary artery pressure. PAOP, pulmonary artery occlusion pressure. PVR, pulmonary vascular resistance. PaO2, partial pressure of oxygen. PaCO2, partial pressure of carbon dioxide. PvO2, mixed venous oxygen pressure. PA, pulmonary artery. Table 3: Cardiopulmonary Exercise Test Parameters Data are presented as median [interquartile range (IQR)] unless otherwise indicated. Rest Anerobic Threshold Peak Exercise VO2, L/min 0.3 [0.2, 0.3] 0.8 [0.7, 0.9] 1.1 [1.01, 1.5] VO2/wt, ml/kg/min 3.2 [2.8, 4.1] 10.4 [8.9, 12.4] 15.1 [13.3, 19.5] O2 pulse, ml/beat 3.7 [2.9, 4.3] 7.4 [6.9, 9.0] 3.3 [3.0, 4.2] SaO 2 , % 98 [97, 98] 98 [95, 100] 97 [96, 99] VO 2 , O 2 consumption; SaO 2 , oxygen saturation. Additional Declarations No competing interests reported. Supplementary Files Tablee1.docx Cite Share Download PDF Status: Published Journal Publication published 11 Mar, 2024 Read the published version in Respiratory Research → Version 1 posted Editorial decision: Revision requested 07 Dec, 2023 Reviews received at journal 06 Nov, 2023 Reviewers agreed at journal 31 Oct, 2023 Reviewers agreed at journal 17 Oct, 2023 Reviewers invited by journal 11 Oct, 2023 Editor assigned by journal 07 Oct, 2023 Submission checks completed at journal 06 Oct, 2023 First submitted to journal 04 Oct, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3411609","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":238348248,"identity":"4a515574-ff12-46ae-870a-789db1fc5aad","order_by":0,"name":"Mona Alotaibi","email":"","orcid":"","institution":"University of California, San Diego Healthcare","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mona","middleName":"","lastName":"Alotaibi","suffix":""},{"id":238348249,"identity":"032d9122-74ad-4c99-b934-e3083284b13e","order_by":1,"name":"Jenny Z. Yang","email":"","orcid":"","institution":"University of California, San Diego Healthcare","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jenny","middleName":"Z.","lastName":"Yang","suffix":""},{"id":238348250,"identity":"738690f0-0e06-42d2-9954-cb11d9adfb35","order_by":2,"name":"Demosthenes G. Papamatheakis","email":"","orcid":"","institution":"University of California, San Diego Healthcare","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Demosthenes","middleName":"G.","lastName":"Papamatheakis","suffix":""},{"id":238348251,"identity":"ef1d2cce-0f99-4f44-aa80-4742683e79bc","order_by":3,"name":"W. Cameron McGuire","email":"","orcid":"","institution":"University of California, San Diego Healthcare","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"W.","middleName":"Cameron","lastName":"McGuire","suffix":""},{"id":238348252,"identity":"02abce50-1b22-4f42-b901-d2e3836d1c40","order_by":4,"name":"Timothy M. Fernandes","email":"","orcid":"","institution":"University of California, San Diego Healthcare","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"M.","lastName":"Fernandes","suffix":""},{"id":238348253,"identity":"74ba7e1e-924f-490b-b5b0-ba87339148b2","order_by":5,"name":"Timothy A. Morris","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYDACZjApwcAvAaQeMByAcqHi2AAPO1SN5AwglZBAjBZ+KMPgBrFa7Jm5Ex9X7rGwN77dfPBD4o87DAbHjz+8wVBhndiAyxZm3s2GZ55JJG67cyxZIiHhGYPBmRxjC4Yz6fi0bJNsOCCRYHYjxwCo5TDQhTxsEoxthwlqsTeekf/5B0QL+zMJxn+EtTBukMhhg9rCYCbB2IBHy2GgX4BaEmfcSDOzSEg7zCMJ8kvCsXRjXFrY+89ufNhwoM6ef0by4xsfbA7L8YFC7EONtSwuLZjWgskEYpWPglEwCkbBKMAKANLbWUccxVVWAAAAAElFTkSuQmCC","orcid":"","institution":"University of California, San Diego Healthcare","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"A.","lastName":"Morris","suffix":""}],"badges":[],"createdAt":"2023-10-04 21:44:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3411609/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3411609/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12931-024-02746-w","type":"published","date":"2024-03-11T15:01:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44450367,"identity":"9c0a5442-c607-4087-af13-2a54482c8404","added_by":"auto","created_at":"2023-10-11 16:35:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":805479,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eO\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e·pulse at rest (O\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e·pulse\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003erest\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e) and at anaerobic threshold (O\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e·pulse\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003eAT\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e). \u0026nbsp;\u003c/strong\u003e\u0026nbsp;A.\u0026nbsp;\u0026nbsp; Normal increase in O\u003csub\u003e2\u003c/sub\u003e·pulse from rest (O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e, solid line) to anaerobic threshold (O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e, dashed line). O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e was 4.5 ml O\u003csub\u003e2\u003c/sub\u003e/beat and O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e was 14.5 ml O\u003csub\u003e2\u003c/sub\u003e/beat.\u0026nbsp; B\u003cstrong\u003e. \u003c/strong\u003ePathologically low increase from O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e to O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e.\u0026nbsp; O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e was 3.8 ml O\u003csub\u003e2\u003c/sub\u003e/beat and O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e was 7.3 ml O\u003csub\u003e2\u003c/sub\u003e/beat.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3411609/v1/fdb212391edec77227cab94e.png"},{"id":44450363,"identity":"7da40e60-cd3d-4569-a112-6fa62c1640e5","added_by":"auto","created_at":"2023-10-11 16:35:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43323,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient selection.\u003c/strong\u003e\u0026nbsp; CPET, cardiopulmonary exercise test; VO\u003csub\u003e2\u003c/sub\u003e, oxygen consumption; AT, anaerobic threshold; TTE, transthoracic echocardiography.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3411609/v1/044b6b0bb64dfcc65a083a09.png"},{"id":44450364,"identity":"1f25adb0-45cf-4f00-ad55-daab88dd31d6","added_by":"auto","created_at":"2023-10-11 16:35:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1641608,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eO\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e·pulse\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003eAT\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e/O\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e·pulse\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003erest\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e compared to TRV\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003epeak\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e to predict stroke volume augmentation.\u003c/strong\u003e\u0026nbsp; \u003cstrong\u003eA.\u003c/strong\u003e\u0026nbsp; O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e determined from CPET data (see text) correlated with stroke volume augmentation from rest to anaerobic threshold (SVA\u003csub\u003eAT\u003c/sub\u003e) measured by right heart catheterization (p \u0026lt; 0.0001).\u0026nbsp; \u003cstrong\u003eB\u003c/strong\u003e The ROC curve of O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e to detect SVA\u003csub\u003eAT\u003c/sub\u003e below the lower limit of normal (LLN) had an area under the ROC curve of 0.92 (SE 0.04, p = 0.0002).\u0026nbsp;\u0026nbsp; \u003cstrong\u003eC.\u003c/strong\u003e \u0026nbsp;Tricuspid regurgitant velocity peak (TRV\u003csub\u003epeak\u003c/sub\u003e) measured by echocardiography did not correlate with SVA\u003csub\u003eAT\u003c/sub\u003e (p =\u0026nbsp; 0.69).\u0026nbsp; \u003cstrong\u003eD. \u003c/strong\u003eThe ROC curve of TRV\u003csub\u003epeak\u003c/sub\u003e to detect SVA\u003csub\u003eAT\u003c/sub\u003e below the LLN had an area of 0.69 (SE 0.10, p = 0.046).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3411609/v1/c59b02e3fba3085b7c5a6367.png"},{"id":52907616,"identity":"08d97cb0-64dd-4fb8-8c18-4121c4cd8507","added_by":"auto","created_at":"2024-03-18 15:13:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":728193,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3411609/v1/3e4470a1-dcce-48f4-a0f2-e812a7c3e2d4.pdf"},{"id":44451172,"identity":"d9c27a05-626f-4a05-b48e-4b3a5e828abd","added_by":"auto","created_at":"2023-10-11 16:43:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15622,"visible":true,"origin":"","legend":"","description":"","filename":"Tablee1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3411609/v1/a194fd0119271f1bce2553df.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cardiopulmonary Exercise Test to Detect Cardiac Dysfunction from Pulmonary Vascular Disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiopulmonary exercise testing (CPET) had been proposed as a noninvasive method to detect pulmonary vascular disease among patients with dyspnea and exercise intolerance after acute pulmonary embolism (PE).\u003csup\u003e1,2\u003c/sup\u003e Pulmonary vascular disease-associated cardiac limitation is manifested by inadequate stroke volume (SV) augmentation in response to exercise.\u003csup\u003e3,4\u003c/sup\u003e CPET has disclosed evidence of inadequate SV augmentation in over half of patients with dyspnea after PE.\u003csup\u003e5\u003c/sup\u003e However, CPET findings suggestive of pathologically decreased SV augmentation have never been validated against the gold standard of direct measurement by right heart catheterization (RHC) in patients with pulmonary vascular disease.\u003c/p\u003e \u003cp\u003eThe \u0026ldquo;direct Fick method\u0026rdquo; of measuring SV by RHC requires simultaneous determination of oxygen consumption rate (VO\u003csub\u003e2\u003c/sub\u003e), mixed venous O\u003csub\u003e2\u003c/sub\u003e content, arterial O\u003csub\u003e2\u003c/sub\u003e content and heart rate. The procedure, though highly accurate, is too invasive and too expensive to evaluate stroke volume augmentation among the vast numbers of patients with post-PE dyspnea. SV, however, is related to VO\u003csub\u003e2\u003c/sub\u003e/heart rate (O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse) and the difference between arterial and mixed venous oxygen content (C\u003csub\u003ea\u0026minus;v\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e) according to the equation\u003c/p\u003e \u003cp\u003eSV\u0026thinsp;=\u0026thinsp;O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse/C\u003csub\u003ea\u0026minus;v\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e \u003cp\u003eIt has been shown among patients with pulmonary vascular disease that the trajectory of O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse increase during exercise does indeed reflect the pattern expected of SV increase.\u003csup\u003e6\u003c/sup\u003e Furthermore, since (C\u003csub\u003ea\u0026minus;v\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e) increases predictably between rest and anaerobic threshold (AT), SV augmentation between rest and AT (SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e) is reflected on CPET by the relative increase in O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse between AT and rest (O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e):\u003c/p\u003e \u003cp\u003eSV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e = (O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e)/(C\u003csub\u003ea\u0026minus;v\u003c/sub\u003eO\u003csub\u003e2_AT\u003c/sub\u003e/C\u003csub\u003ea\u0026minus;v\u003c/sub\u003eO\u003csub\u003e2_rest\u003c/sub\u003e).\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe retrospectively reviewed our clinical experience with combined CPET and RHC examinations to determine whether, in patients with suspected pulmonary vascular disease, O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e, measured noninvasively by CPET predicts abnormally low SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e, measured invasively by RHC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003e We reviewed the results of simultaneous RHC and CPET among consecutive patients suspected of having pulmonary vascular disease who were referred to the University of California, San Diego from January 2018 through February 2023. RHC-CPET was performed based on the clinical judgement of the pulmonary vascular specialist. Among patients with more than one study, we evaluated only the first study. Inclusion criteria were: (1) measurement, at rest, of heart rate (HR\u003csub\u003erest\u003c/sub\u003e), cardiac output (Q\u003csub\u003erest\u003c/sub\u003e) by the direct Fick method and O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e; (2) measurement, at an independently determined AT point, of O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e; and (3) measurement, when VO\u003csub\u003e2\u003c/sub\u003e was within 20% of the VO\u003csub\u003e2\u003c/sub\u003e at AT, of HR\u003csub\u003eAT\u003c/sub\u003e and Q\u003csub\u003eAT\u003c/sub\u003e. There were no exclusion criteria. The University of California, San Diego Institutional Review Board approved the study (IRB #171888).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eRight heart catheterization and SVA\u003csub\u003eAT\u003c/sub\u003e\u003c/h2\u003e \u003cp\u003eRHC was performed at rest and during exercise as previously described.\u003csup\u003e8\u003c/sup\u003e A radial artery catheter and a pulmonary artery catheter were inserted in the cardiac catheterization laboratory while patients were in the supine position. Right atrial, right ventricular, pulmonary artery, and pulmonary artery occlusion pressure were measured in succession. Once a stable respiratory quotient was observed with the patient at rest, heart rate was recorded, and cardiac output was determined with the direct Fick method from the measured VO2 and simultaneous radial artery and pulmonary artery blood gases.\u003c/p\u003e \u003cp\u003eThe subjects then performed incrementally increased exercise on a supine cycle ergometer (Medical Positioning, Inc.), as described below. Heart rate and cardiac output measurements were repeated in a similar fashion during exercise at point near anerobic threshold (as determined in real-time by a change in the slope VCO2 versus VCO2) and again near peak exertion.\u003c/p\u003e \u003cp\u003eHemodynamic data were collected without knowledge of the CPET results. SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e was calculated as\u003c/p\u003e \u003cp\u003eSV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e = (Q\u003csub\u003eAT\u003c/sub\u003e / HR\u003csub\u003eAT\u003c/sub\u003e) / (Q\u003csub\u003erest\u003c/sub\u003e / HR\u003csub\u003erest\u003c/sub\u003e),\u003c/p\u003e \u003cp\u003ewhere Q\u003csub\u003eAT\u003c/sub\u003e and Q\u003csub\u003erest\u003c/sub\u003e represent cardiac output at anaerobic threshold and at rest, respectively, and HR\u003csub\u003eAT\u003c/sub\u003e and HR\u003csub\u003erest\u003c/sub\u003e represent heart rate at anaerobic threshold and at rest, respectively. We pre-specified the lower limit of normal for SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e based right heart catheterization data from healthy volunteers, in whom stroke volume increased by 38.8% (SD 5.2%) between rest and AT.\u003csup\u003e7\u003c/sup\u003e We arbitrarily selected the mean minus two times the standard deviation from that experiment (128%) as the SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e lower limit of normal (LLN) for the current study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCardiopulmonary exercise test determination of O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e and O2\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e\u003c/h2\u003e \u003cp\u003eSimultaneously with the RHC, we performed incremental symptom-limited CPET with the patients on a recumbent bicycle, using a stepwise exercise protocol to produce a uniform increase in work rate and metabolic energy expenditure per incremental step. O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e was determined during steady state rest with a V-Max metabolic cart (CareFusion, San Diego, CA) or a Ultima Cardio2 metabolic cart (MGC Diagnostics, St Paul, MN) from VO\u003csub\u003e2\u003c/sub\u003e, measured through breath-by-breath analysis of inspired and expired gases and heart rate, measured by continuous electrocardiography (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnaerobic threshold was determined by the V-slope method by a board-certified pulmonologist (TM) without knowledge of the RHC results. O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e was determined retrospectively during the 20-second interval containing the anaerobic threshold point (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEchocardiography\u003c/h2\u003e \u003cp\u003eFor comparison, peak tricuspid regurgitation velocity (TRV\u003csub\u003epeak\u003c/sub\u003e) and other signs of pulmonary vascular disease\u003csup\u003e9\u003c/sup\u003e were recorded from echocardiograms that had been performed within six months of the combined CPET-RHC studies. In addition, the echocardiographic results were categorized as high- or intermediate-risk vs low-risk, according to the recommendations of the European Society of Cardiology and the European Respiratory Society (ESC/ERS) Task Force for the Diagnosis and Management of Acute Pulmonary Embolism\u003csup\u003e10\u003c/sup\u003e and the ESC/ERS Task Force for the Diagnosis and Treatment of Pulmonary Hypertension.\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables are presented as mean (+/- standard deviation) or median and interquartile range [IQR]. Categorical variables are presented as number (%). Pearson correlation was used to compare O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e to SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e and to compare TRV\u003csub\u003epeak\u003c/sub\u003e to SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e. O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e and TRV\u003csub\u003epeak\u003c/sub\u003e were also linearly regressed on SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e. Receiver operating characteristic curves were plotted to compare the sensitivities and specificities of O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e and TRV\u003csub\u003epeak\u003c/sub\u003e for detecting SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e below the lower limit of normal (LLN\u0026thinsp;=\u0026thinsp;1.28).\u003csup\u003e7\u003c/sup\u003e We defined 90% as an acceptable sensitivity for a screening test to detect SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e below the LLN. Statistical calculations were performed with Prism version 9 (GraphPad Software, San Diego CA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eStudy population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDuring the study period, 83 simultaneous RHC and CPET tests were performed. Forty-seven tests were not included because blood was not sampled from the systemic artery (n=8) or pulmonary artery (n=1) for direct Fick cardiac output measurement; anaerobic threshold was not reached or was indeterminate (n=8); or cardiac output was not measured during exercise while the VO\u003csub\u003e2\u003c/sub\u003e was within 20% of VO\u003csub\u003e2\u003c/sub\u003e at anaerobic threshold (n=30). \u0026nbsp;Thirty-six tests met the inclusion criteria and were included in the analysis (Fig. 2). \u0026nbsp;The demographics and hemodynamics of the excluded patients were not different from the included patients (Table e1).\u003c/p\u003e\n\u003cp\u003eIncluded patients were 56.5 [40.25, 66] years of age and had body mass index (BMI) of 28 [24.1, 32.5] kg/m\u003csup\u003e2\u003c/sup\u003e (Table 1). \u0026nbsp; There were 11 (30.6%) men and 25 (69.4%) women. \u0026nbsp;12 patients (33.3%) had co-existing cardiopulmonary comorbidities. \u0026nbsp;All patients exercised to the point of volitional exhaustion without adverse effects. \u0026nbsp;The distribution of hemodynamic measurements and CPET parameters are illustrated in Tables 2 and 3, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRelationship between O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e and SVA\u003csub\u003eAT\u003c/sub\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFigure 3A illustrates a statistically significant linear correlation between O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e and SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e (r = 0.72, 95% CI 0.52, 0.85; p \u0026lt; 0.0001). \u0026nbsp;Linear regression yielded a slope of 0.51 (95% CI 0.48, 0.55) between SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e and O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e. \u0026nbsp;The LLN for SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e (1.28) corresponded to O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e of 2.5 (95% CI 2.3, 2.7). \u0026nbsp;In contrast, Figure 3C shows no significant correlation between TRV\u003csub\u003epeak\u003c/sub\u003e and SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e (r = -0.09, 95% CI -0.47, 0.33; p \u0026lt; 0.69). \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe area under the receiver operating characteristic curve (AUROC) of O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e for detecting SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e below the LLN (Fig 3B) was 0.92 (SE 0.04, p = 0.0002). \u0026nbsp; The AUROC 95% CI was 0.832 to 1.00. \u0026nbsp;O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%). \u0026nbsp;O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e of less than 2.2 was only 74 % sensitive (95% CI 55.3%, 86.8%) but 100% specific (95% CI 70.1%, 100%).\u003c/p\u003e\n\u003cp\u003eThe AUROC of TRV\u003csub\u003epeak\u003c/sub\u003e to detect SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e below the LLN (Fig. 3D) was 0.69 (SE 0.10, p = 0.12). \u0026nbsp;The AUROC 95% CI was 0.495 to 0.889, which includes the nondiscriminatory value of 0.5. \u0026nbsp;No value of TRV\u003csub\u003epeak\u003c/sub\u003e had a sensitivity of 90% or higher. \u0026nbsp;Echocardiography meeting the ESC/ERS criteria\u003csup\u003e10\u003c/sup\u003e for intermediate- or high-risk \u0026nbsp;(TRV\u003csub\u003epeak\u003c/sub\u003e \u0026gt;2.8 and/or presence of two other pulmonary hypertension signs\u003csup\u003e9\u003c/sup\u003e) was only 23.0% sensitive (95% CI 11.0%, 42.0%) but 100% specific (95% CI 64.6%, 100%) for detecting SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e below the LLN.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe validated the accuracy of O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e to predict SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e in a consecutive series of patients receiving combined CPET and RHC for the clinical evaluation of dyspnea potentially related to pulmonary vascular disease. We derived a cutoff of 2.6 for O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e to predict SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e less than the LLN. We observed a highly significant linear relationship between O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e and SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e, with a slope that corresponds with previous CPET-RHC comparisons among healthy subjects and among patients with various severities of heart failure.\u003csup\u003e7,11–15\u003c/sup\u003e. Although O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e enables merely an estimate of the RHC measurement of SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e, the correlation between the two is comparable to or even superior to the correlation between different invasive methods of measuring stroke volume by RHC.\u003csup\u003e16–19\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSV augmentation is an important adaptation to exercise that helps increase cardiac output and maintain organ perfusion during increased oxygen utilization.\u003csup\u003e12\u003c/sup\u003e Increased venous pressure during exercise enhances right ventricular end-diastolic volume\u003csup\u003e20\u003c/sup\u003e and normally improves contractility.\u003csup\u003e21\u003c/sup\u003e SV rises incrementally as exercise proceeds and reaches a plateau near AT.\u003csup\u003e7,12,22–24\u003c/sup\u003e In healthy persons, there is an approximately 40% increase in SV by the time AT is reached.\u003csup\u003e7\u003c/sup\u003e The advantage to considering SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e, rather than SV\u003csub\u003eAT\u003c/sub\u003e alone, is that the ratio controls for demographic factors (body size, age, sex, etc.) that typically influence SV.\u003c/p\u003e \u003cp\u003ePulmonary vascular disease leads to elevated right ventricular end-diastolic volume and impaired contractility at rest, which impedes the normal adaptation to exercise.\u003csup\u003e21\u003c/sup\u003e As a result, SV augmentation is markedly decreased\u003csup\u003e3,4\u003c/sup\u003e Residual pulmonary vascular obstruction limits SV augmentation, increases pulmonary artery resistance and compromises right ventricular function.\u003csup\u003e25,26\u003c/sup\u003e Since SV augmentation substantially improves among CTEPH patients after pulmonary artery thromboendarterectomy, it is reasonable to attribute the defect to pulmonary vascular obstruction itself.\u003csup\u003e4\u003c/sup\u003e Furthermore, insufficient SVA in response to exercise predicts mortality from pulmonary hypertension more accurately than any other exercise parameter and enhances the accuracy of mortality prediction above the six minute walking distance alone.\u003csup\u003e27\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough CTEPH is present in only a small fraction of patients with dyspnea after PE,\u003csup\u003e28\u003c/sup\u003e less severe pulmonary vascular disease causes respiratory symptoms,\u003csup\u003e29\u003c/sup\u003e hypoxemia,\u003csup\u003e30–32\u003c/sup\u003e gas exchange deficits\u003csup\u003e31,33,34\u003c/sup\u003e and exercise intolerance.\u003csup\u003e35\u003c/sup\u003e Residual pulmonary vascular obstruction is associated with the risk of progression to CTEPH.\u003csup\u003e36\u003c/sup\u003e In our previous series of CPET for patients with long-term dyspnea after acute pulmonary embolism, low O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e corresponded to residual pulmonary artery obstruction.\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAmong symptomatic post-pulmonary embolism patients, low O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e measured noninvasively during CPET suggests inadequate SV augmentation because of residual pulmonary vascular occlusion.\u003csup\u003e5\u003c/sup\u003e Validation that O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e accurately reflects SV augmentation enables CPET to be an informative and practical noninvasive tool to help distinguish between pulmonary vascular disease and deconditioning or anxiety (in the absence of physiological defects) among the large number of patients with dyspnea after pulmonary embolism.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur results compliment the results of Held et al. and of McCabe et al., who disclosed abnormal CPET findings in a majority of patients in whom CTED or CTEPH had been confirmed by RHC.\u003csup\u003e37,38\u003c/sup\u003e As was the case in our study, echocardiography (including TRV\u003csub\u003epeak\u003c/sub\u003e) was unable to detect pulmonary vascular disease in 31% of CTEPH patients.\u003csup\u003e37\u003c/sup\u003e The insensitivity likely refects the fact that echocardiography is routinely performed at rest, which may not reflect defects that are manifested only during exercise. However, we recognize that echocardiography typically preceded RHC-CPET, at times by several months. It is possible that the difference between echocardiographic and CPET results were influenced by disease progression among some patients.\u003c/p\u003e \u003cp\u003eNotably, CPET data from CTED and CTEPH patients reported by Held et al. and McCabe et al reflected ventilatory inefficiency, presumably based on ventilation/perfusion mismatching.\u003csup\u003e37,38\u003c/sup\u003e We observed similar ventilatory inefficiency in our patients, which we are investigating in a separate study. The current study focuses on the ability of O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e, to reflect stroke volume augmentation itself. However, we anticipate that both factors are likely implicated in pulmonary vascular disease after acute PE.\u003csup\u003e5,39\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSince acute pulmonary embolism occurs in about 63/100,000 persons per year,\u003csup\u003e40\u003c/sup\u003e up to half of whom report chronic dyspnea,\u003csup\u003e41–43\u003c/sup\u003e the method we validated could detect SV augmentation limitation due to pulmonary vascular disease in a large number of at-risk patients.\u003csup\u003e28\u003c/sup\u003e It is more practical than RHC and more sensitive than echocardiography. Since our patients ranged from normal to very poor cardiopulmonary reserve during exercise, our results suggest that O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e would reflect SV augmentation across a wide spectrum of dysfunction.\u003c/p\u003e \u003cp\u003eBesides acute pulmonary embolism, there are numerous risk factors associated with pulmonary vascular disease, including scleroderma and other connective tissue diseases. In these at-risk patients, symptoms begin with dyspnea on exertion, but pulmonary hypertension may not be present at rest. Non-invasive CPET to screen for decreased exercise-related stroke volume augmentation by detecting impaired O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e has the potential to identify these patients as well, earlier in their disease course.\u003c/p\u003e \u003cp\u003eESC/ERS guidelines recommend transthoracic echocardiography as an initial test to evaluate dyspnea on exertion after pulmonary embolism.\u003csup\u003e10\u003c/sup\u003e However, while TTE can be useful as a screen for chronic thromboembolic pulmonary hypertension (CTEPH), it may not be the best approach for evaluating patients who are limited by persistent perfusion defects that cause exercise-induced pulmonary hypertension. Our present research has shown that tricuspid regurgitant velocity peak is less sensitive than non-invasively measured O2·pulse\u003csub\u003eAT\u003c/sub\u003e/O2·pulse\u003csub\u003erest\u003c/sub\u003e in detecting directly measured SVA AT below the lower limit of normal. Therefore, we recommend non-invasive cardiopulmonary exercise testing (CPET) as the first step in evaluating dyspnea after PE.\u003c/p\u003e \u003cp\u003eLike other studies of CPET and RHC for pulmonary vascular disease,\u003csup\u003e37,38\u003c/sup\u003e our study is limited by its relatively small size and its retrospective nature. In addition, because O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e, reflects SV augmentation at AT, our study included only RHC tests that measured both SV\u003csub\u003erest\u003c/sub\u003e and SV near AT. Estimation of SV augmentation from O\u003csub\u003e2\u003c/sub\u003e·pulse ratios at other times would have been erroneous due to changes in oxygen extraction and heart rate during exercise above AT.\u003csup\u003e7,12,22–24\u003c/sup\u003e Nevertheless, with careful attention to technique, SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e could serve as a standard by which to evaluate SV augmentation during exercise.\u003c/p\u003e \u003cp\u003eA limitation of our study is that we selected the LLN for SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e based on RHC-CPET studies performed on young, healthy subjects during upright cycling. Supine position increases venous return at rest and may lower the relative increase in diastolic volume during exercise that contributes to the SV response.\u003csup\u003e20\u003c/sup\u003e Further studies are needed to determine if the predicted and LLN for SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e should be different between upright and recumbent CPETs.\u003c/p\u003e \u003cp\u003eChronotropic incompetence may confound the clinical implication of stroke volume augmentation, since slow heart rates during exercise would allow more time for diastolic filling and potentially dampen the effect of cardiac dysfunction on stroke volume during exercise. However, it is unlikely that chronotropic incompetence played a substantial role in the current study, since heart rates were similar between subjects with normal SVA (110.3 +/- 19.5) and those with low SVA (107.2 +/- 17.4).\u003c/p\u003e \u003cp\u003eThe CPET-based estimation of SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e that we validated during right heart catheterization may be useful as a stand-alone test in other settings. For example, the method may be used for the noninvasive screening of ambulatory patients with a variety of cardiac and pulmonary disorders for exercise-related heart dysfunction. The method would help quantify cardiac adaptation to exercise in patients with known or suspected heart failure.\u003c/p\u003e \u003cp\u003eWe speculate that deficient stroke volume augmentation from various types of heart failure (right side or left side, systolic or diastolic) will have similar increases in C\u003csub\u003ea−v\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e between rest and AT and therefore similar effects of SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e on O2·pulse\u003csub\u003eAT\u003c/sub\u003e/O2·pulse\u003csub\u003erest\u003c/sub\u003e.\u003csup\u003e7\u003c/sup\u003e However, we would not expect O2·pulse\u003csub\u003eAT\u003c/sub\u003e/O2·pulse\u003csub\u003erest\u003c/sub\u003e to reflect SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e accurately among patients with myopathies that cause poor O2 extraction (e.g. mitochondrial enzyme defects), since the C\u003csub\u003ea−v\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e might not change in a predictable fashion at AT. Although the current study did not include such patients, it is possible that myopathies could be differentiated from stroke volume augmentation defects by differences in O2·pulse trajectories subsequent to AT. Degani-Costa et al. reported flattening of the O2·pulse trajectory (and upward deflection of the heart rate vs VO2 plot) during the later portions of exercise among subjects with pulmonary hypertension but not among those with mitochondrial myopathies.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe hope that our results will open a line of investigation about the role of this technique in the management of patients at risk of right ventricular dysfunction from pulmonary vascular disease. The technique may be particularly helpful in patients in whom dysfunction occurs during exercise but is not apparent at rest. Also, because SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e reflects overall cardiac adaptation to exercise, it is a potential predictor of poor outcomes that may supplement the roles of peak VO\u003csub\u003e2\u003c/sub\u003e, VO\u003csub\u003e2\u003c/sub\u003e at AT and V\u003csub\u003eE\u003c/sub\u003e/VCO\u003csub\u003e2\u003c/sub\u003e. Future research would be needed to ascertain the clinical utility of using O2·pulse\u003csub\u003eAT\u003c/sub\u003e/O2·pulse\u003csub\u003erest\u003c/sub\u003e to evaluate patients with dyspnea of unknown origin.\u003c/p\u003e "},{"header":"Summary","content":"\u003cp\u003eWe validated the accuracy of O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e·pulse\u003csub\u003erest\u003c/sub\u003e, measured noninvasively by CPET, compared to invasive measurement of SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e during RHC. We derived a cutoff value of 2.6, which should be validated in future studies. Our results suggest that CPET can be used to evaluate SV augmentation in symptomatic patients at risk for pulmonary vascular disease, such as those with dyspnea after acute pulmonary embolism, to detect early compromise of the right ventricle.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAT: anaerobic threshold; CPET: cardiopulmonary exercise test; HR\u003csub\u003eAT\u003c/sub\u003e: heart rate at anaerobic threshold; HR\u003csub\u003erest\u003c/sub\u003e: heart rate at rest; Q\u003csub\u003eAT\u003c/sub\u003e: cardiac output at anaerobic threshold; Q\u003csub\u003erest\u003c/sub\u003e: cardiac output at rest; RHC: right heart catheterization; SVA: stroke volume augmentation; SVA\u003csub\u003eAT\u003c/sub\u003e: stroke volume augmentation at anaerobic threshold measured by RHC; O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003e:\u0026nbsp;\u003c/sub\u003eoxygen consumption rate divided by heart rate; \u0026nbsp;O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e: O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse at rest; \u0026nbsp;O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e: O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse at anaerobic threshold.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthical Approval\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe University of California, San Diego Institutional Review Board approved the study (IRB #171888).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere was no external funding for this study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDeidentified data relevant to this study is available upon request to the corresponding author.\u003c/p\u003e\u003cp\u003eSummary of conflict-of-interest statements: The authors report no conflicts of interest and no financial support relevant to this work.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthor contribution statement: TAM and TMF contributed equally to the conception, design and execution of the research. Material preparation and data collection performed by JZY, TMF, DGP, MA, and WCM. Data analysis performed by TAM and MA. All authors contributed to writing, editing, and approved the manuscript. \u003cstrong\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcknowledgements: The authors thank, Brenda G. Money, Alicia E. Salcido, Sandee Lombardi and Cynthia Rodriguez for their performance of the technical aspects of the invasive CPETs and their expertise in processing the CPET data. \u0026nbsp;We thank Khadizhat Dakaeva for her careful attention to detail in organizing the data for publication. \u0026nbsp;The authors also thank Drs. William Stringer and Atul Malhotra for critical review of the manuscript and helpful comments prior to submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMorris TA, Fernandes TM, Channick R. 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Functional and Exercise Limitations After a First Episode of Pulmonary Embolism: Results of the ELOPE Prospective Cohort Study. \u003cem\u003eChest. \u003c/em\u003e2017;151(5):1058-1068.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eTable1: Patient Characteristics (n=36)\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are presented as median [interquartile range] or count (percent) unless otherwise indicated. \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"378\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient Characteristics\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003emn1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIncluded\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge, years, median [IQR]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e56.5 [40.25, 66]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28 [24.1, 32.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFinal Diagnosis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Pulmonary Arterial Hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Left Ventricular failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;CTED/CTEPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHistory of Pulmonary embolism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCoexisting cardiovascular disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCoexisting cardiovascular disease type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Arrhythmias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Coronary artery disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCoexisting lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCoexisting lung disease type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Asthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Diffuse parenchymal lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Obstructive sleep apnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eBMI, body mass index. \u0026nbsp;CTED, chronic thromboembolic disease. \u0026nbsp;CTEPH, chronic thromboembolic pulmonary hypertension. \u003cstrong\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eTable 2: Hemodynamic Parameters at rest, anerobic threshold and peak exercise.\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are presented as median [interquartile range (IQR)] unless otherwise indicated. \u0026nbsp; *Cardiac output was calculated by the direct Fick method. \u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRest\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnerobic threshold\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePeak exercise\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003emean arterial blood pressure, mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e100.5 [92, 108]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e118.5 [112, 126]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e128 [116, 133]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003emean PAP, mmHg \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e19 [15, 23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e32 [22.8, 34.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e38 [30.5, 42.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003ePAOP, mmHg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e12 [10, 14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e18 [15.3, 20]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e22 [18, 26]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003ePVR, Wood Units\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e1.1 [0.5, 2.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e1.068 [0.69, 1.67]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e0.95 [0.7, 1.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003eCardiac output, L/min\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e6 [5, 8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e10.2 [9.0, 13.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e13.2 [11.3, 15.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003eCardiac index, L/min/m2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e3 [3, 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e5.9 [4.4, 7.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e6.8 [6.1, 7.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003eStroke volume, ml/beat \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e91.4 [65.4, 122.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e96.2 [85.7, 124.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e98.1 [84.7, 120.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e86 [78, 97]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e79 [72, 95.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e79 [72.5, 91.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003ePaCO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e38 [34, 40]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e38 [35.3, 41.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e36 [33, 40]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003ePvO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e39 [36, 43]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e30.5 [27.2, 33]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e28 [24, 30]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003eArterial saturation, %\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e98 [97, 99]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e97.4 [95.4, 98.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e97.6 [95.2, 98.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003ePA saturation, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e76 [71, 79]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e56.8 [50.1, 59.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e46.7 [38.9, 51.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.11556982343499%\" valign=\"top\"\u003e\n \u003cp\u003eHeart Rate, BPM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.545746388443018%\" valign=\"top\"\u003e\n \u003cp\u003e75 [65, 81]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.187800963081862%\" valign=\"top\"\u003e\n \u003cp\u003e109 [96.5,116]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.150882825040128%\" valign=\"top\"\u003e\n \u003cp\u003e139.5 [115.2, 147.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePAP, pulmonary artery pressure. PAOP, pulmonary artery occlusion pressure. PVR, pulmonary vascular resistance. PaO2, partial pressure of oxygen. PaCO2, partial pressure of carbon dioxide. PvO2, mixed venous oxygen pressure. PA, pulmonary artery. \u003cu\u003e\u003c/u\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eTable 3: Cardiopulmonary Exercise Test Parameters\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are presented as median [interquartile range (IQR)] unless otherwise indicated.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.719449225473323%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRest\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.67814113597246%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnerobic Threshold\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePeak Exercise\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.719449225473323%\" valign=\"top\"\u003e\n \u003cp\u003eVO2, L/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e0.3 [0.2, 0.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.67814113597246%\" valign=\"top\"\u003e\n \u003cp\u003e0.8 [0.7, 0.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e1.1 [1.01, 1.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.719449225473323%\" valign=\"top\"\u003e\n \u003cp\u003eVO2/wt, ml/kg/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e3.2 [2.8, 4.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.67814113597246%\" valign=\"top\"\u003e\n \u003cp\u003e10.4 [8.9, 12.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e15.1 [13.3, 19.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.719449225473323%\" valign=\"top\"\u003e\n \u003cp\u003eO2 pulse, ml/beat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e3.7 [2.9, 4.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.67814113597246%\" valign=\"top\"\u003e\n \u003cp\u003e7.4 [6.9, 9.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e3.3 [3.0, 4.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.719449225473323%\" valign=\"top\"\u003e\n \u003cp\u003eSaO\u003csub\u003e2\u003c/sub\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e98 [97, 98]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.67814113597246%\" valign=\"top\"\u003e\n \u003cp\u003e98 [95, 100]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.301204819277107%\" valign=\"top\"\u003e\n \u003cp\u003e97 [96, 99]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eVO\u003csub\u003e2\u003c/sub\u003e, O\u003csub\u003e2\u003c/sub\u003e consumption; SaO\u003csub\u003e2\u003c/sub\u003e, oxygen saturation.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"cardiopulmonary exercise test (CPET), echocardiography, pulmonary embolism, stroke volume augmentation, pulmonary vascular disease","lastPublishedDoi":"10.21203/rs.3.rs-3411609/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3411609/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e with RHC-determined SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e. We evaluated the sensitivity and specificity of O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e to detect SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRV\u003csub\u003epeak\u003c/sub\u003e) with SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFrom July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse and SV at rest and at AT. O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e correlated highly with SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e (r\u0026thinsp;=\u0026thinsp;0.72, 95% CI 0.52, 0.85; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), whereas TRV\u003csub\u003epeak\u003c/sub\u003e did not (r = -0.09, 95% CI -0.47, 0.33; p\u0026thinsp;\u0026lt;\u0026thinsp;0.69). The AUROC to detect SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e below the LLN was significantly higher for O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e (0.92, SE 0.04; p\u0026thinsp;=\u0026thinsp;0.0002) than for TRV\u003csub\u003epeak\u003c/sub\u003e (0.69, SE 0.10; p\u0026thinsp;=\u0026thinsp;0.12). O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SV\u003csub\u003eAT\u003c/sub\u003e/SV\u003csub\u003erest\u003c/sub\u003e.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003eAT\u003c/sub\u003e/O\u003csub\u003e2\u003c/sub\u003e\u0026middot;pulse\u003csub\u003erest\u003c/sub\u003e may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism.\u003c/p\u003e","manuscriptTitle":"Cardiopulmonary Exercise Test to Detect Cardiac Dysfunction from Pulmonary Vascular Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-11 16:35:38","doi":"10.21203/rs.3.rs-3411609/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2023-12-07T16:02:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-11-06T18:26:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"60e209c1-063a-4f33-b5d7-9003ef595f3b","date":"2023-10-31T16:07:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5bed111e-4faa-483f-b4f8-af7eb4f9b631","date":"2023-10-17T11:15:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-11T09:47:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-07T12:33:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-10-06T14:28:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Respiratory Research","date":"2023-10-04T21:32:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4678deb8-01ed-4cbc-9e5b-d5c4d1ec42ff","owner":[],"postedDate":"October 11th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-18T15:09:22+00:00","versionOfRecord":{"articleIdentity":"rs-3411609","link":"https://doi.org/10.1186/s12931-024-02746-w","journal":{"identity":"respiratory-research","isVorOnly":false,"title":"Respiratory Research"},"publishedOn":"2024-03-11 15:01:18","publishedOnDateReadable":"March 11th, 2024"},"versionCreatedAt":"2023-10-11 16:35:38","video":"","vorDoi":"10.1186/s12931-024-02746-w","vorDoiUrl":"https://doi.org/10.1186/s12931-024-02746-w","workflowStages":[]},"version":"v1","identity":"rs-3411609","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3411609","identity":"rs-3411609","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}