Holistic integrative interpretation for similarities and differences of cardiopulmonary exercise testing (CPET) pathophysiological characteristics in patients with left and right heart failure

Introduction

In the theory of Holistic Integrative Physiology and Medicine (HIPM), the intricate integration of respiration, circulation, and metabolism is fundamental to regulating the normal functioning of an organism and maintaining the stability of its overall functions (1-4). Patients with heart failure have pathophysiological characteristics that are better explained by the HIPM theory. Left heart failure (LHF) is a syndrome primarily induced by impaired left ventricular function, commonly resulting from myocardial ischemia, hypertension, and dilated cardiomyopathy (5). It is characterized by the left ventricle’s inability to supply adequate output to meet the demands of skeletal muscles during exercise while maintaining normal filling pressures. In LHF, increased left atrial pressure and pulmonary venous pressure lead to a sequential reversal of pressure through the capillaries. This reversal can escalate pulmonary artery pressure, potentially leading to the development of right heart failure (RHF) as a secondary complication of LHF. The diminished cardiac ejection capacity and increased pressure in the left atrium, pulmonary veins, and capillaries contribute to heightened resistance in the pulmonary circulation, ultimately progressing to chronic pulmonary congestion (1,6). This pulmonary congestion reduces lung compliance, augments respiratory work, and results in abnormal respiratory patterns (7). Consequently, left heart insufficiency destabilizes respiratory regulation, often manifesting as oscillatory breathing (OB), thereby highlighting the interconnectedness of cardiac and respiratory systems within the HIPM.

RHF is characterized as a rapidly progressive syndrome resulting from systemic stasis due to impaired right ventricular (RV) function. This impairment can stem from either compromised RV filling or reduced ejection of blood (8,9). One of the primary causes of RHF is prolonged pulmonary hypertension (PH), which leads to the enlargement of the right ventricle, tricuspid regurgitation, and ultimately, a decrease in cardiac output (CO). Patients with RHF who also suffer from PH exhibit a form of pulmonary vasculopathy. This condition is marked by increased pulmonary vascular resistance, further exacerbating the heart’s ability to pump efficiently (10). During physical exertion, such patients often experience a unique physiological response: the pressure in the right atrium surpasses that in the left atrium. This pressure gradient causes venous blood to be diverted through the foramen ovale into systemic circulation, triggering arterial chemoreceptors and leading to hyperventilation (11). In severe cases of RHF during exercise, an exercise-induced right-to-left shunting (R-LShunt) can occur, accompanied by abnormal patterns of gas exchange. This R-LShunt allows deoxygenated blood to bypass the lungs and enter systemic circulation, further complicating the respiratory and circulatory challenges in these patients.

Cardiopulmonary exercise testing (CPET) stands as the most objective and gold-standard method for evaluating exercise capacity in patients with heart failure, offering invaluable insights into cardiovascular, pulmonary, and skeletal muscle metabolic functions (12,13). Recognizing its diagnostic and prognostic utility, we employed CPET to quantitatively investigate the pathophysiological characteristics of LHF and RHF. Numerous studies have validated the prognostic significance of peak oxygen uptake (V˙O2) in patients with heart failure (14-16). However, Gitt et al. have identified a combination of anaerobic threshold (AT)-phase V˙O2<11 mL/kg/min and carbon dioxide ventilatory efficiency (V˙E/V˙CO2) slope >34 as a more robust predictor of chronic heart failure outcomes, specifically indicating a higher risk of early mortality (17). Further expanding on this, Sun et al. demonstrated that the lowest ratio of minute ventilation to carbon dioxide output (lowest V˙E/V˙CO2) emerged as the optimal single predictor of mortality. They also noted that combining lowest V˙E/V˙CO2 with other parameters like peak V˙O2, AT, and oxygen pulse (V˙O2/HR), particularly when paired with OB, enhances the predictive power for morbidity and mortality in heart failure patients (18,19). Moreover, CPET has been acknowledged in studies, such as one involving 71 subjects with primary PH, as a safe, non-invasive, and cost-effective technique for detecting R-LShunt (11,20,21). All patients with heart failure exhibited exercise intolerance. In CPET, several studies have demonstrated that patients with LHF experience a significant reduction in peak oxygen uptake (14,22,23). Moreover, patients with more severe heart failure display a higher V˙E/V˙CO2 slope (24). According to the Society for Heart Lung Transplantation’s listing criteria for heart transplantation, a V˙E/V˙CO2 slope greater than 35 is considered one of the determinants for transplantation eligibility (25). Patients with left ventricular systolic heart failure exhibit an abnormal respiratory pattern—OB during CPET, which is closely associated with increases in cardiac index (CI) and filling pressure (26). Additionally, patients with right heart dysfunction due to PH demonstrate a significant rise in the V˙E/V˙CO2 slope during CPET, attributed to elevated pulmonary vascular resistance (27). However, CPET has also been shown to be an effective method for detecting R-LShunt induced by exercise in patients with PH (11). Despite its established utility, there remains a gap in the literature regarding the analysis of CPET key parameters in LHF and RHF, particularly from a holistic integrative perspective. Our study seeks to bridge this gap by analyzing the similarities and differences in the CPET profiles of LHF and RHF, thereby contributing to a more nuanced understanding of these conditions within the theory of HIPM.

Our study aimed to understand the different pathophysiological manifestations by analyzing the changes in gas exchange during exercise and the mechanisms affecting respiration, circulation, and metabolism in patients with LHF and RHF. By characterizing the performance of LHF and RHF during CPET, it is also possible to make a preliminary assessment of the severity of heart failure and monitor the progression of the disease. A key aspect of our analyses involved examining specific pathophysiological phenomena, namely differences in the incidence of OB in LHF and R-LShunt in RHF. By delving into these specific conditions, we aimed to gain a deeper understanding of the distinct exercise pathophysiology in LHF and RHF. This approach allowed us to assess the extent to which OB and R-LShunt contribute to the functional exercise limitations observed in these heart failure subtypes, thereby enriching our comprehension of their unique clinical manifestations and potential therapeutic considerations. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-519/rc).

Methods

Subjects

This retrospective study enrolled 224 patients with heart failure who were treated at Fuwai Hospital between 2018 and 2023. The patient cohort comprised 123 individuals with LHF and 101 with RHF. Additionally, 81 normal subjects (NS) were included as a control group. Heart failure was diagnosed based on the guidelines of Diagnosis and Treatment of Heart Failure in China 2024 (28). All patients with heart failure were clinically stable and classified within New York Heart Association (NYHA) class II–IV. Notably, all patients with RHF were diagnosed with PH according to the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) expert consensus document (29). The exclusion criteria included the acute stage of heart failure, unstable angina, acute myocardial infarction, malignant arrhythmia, hemodynamic instability, and intermittent claudication. The group of NS consisted of healthy individuals who were not diagnosed with cardiac, pulmonary vascular, or other conditions impacting cardiorespiratory performance during the physical examination. Clinical data collection for both LHF and RHF patients included echocardiography, assessment using the NYHA classification, laboratory tests, medication history, comorbidities, and detailed CPET parameters. Specifically, for the RHF patients with PH, right heart catheterization tests were performed. All examinations of the patients were completed within 2 weeks of hospitalization. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The retrospective study was approved by the Ethics Committee of Fuwai Hospital (No. 2023-2236). Individual consent was waived due to the retrospective nature of this study.

In our study, we implemented specific criteria to ensure the accuracy and relevance of our data. Patients with incomplete datasets or implausible CPET data were excluded from the analysis. This included patients with unique clinical conditions such as those who had undergone cardiac transplantation, as well as those classified under the NYHA class I. Furthermore, the process of estimating and diagnosing heart failure in patients was comprehensive and multifaceted. It involved a thorough evaluation of each patient’s medical history, physical examination findings, echocardiographic data, and relevant laboratory results.

CPET measurements

All patients and NS underwent CPET, conducted by the American Thoracic Society/American College of Chest Physicians Statement on CPET. The CPETs were performed using the Quark PFT Ergo model from Cosmed (COSMED S.R.L, Pavona, Italy). Before each testing session, a comprehensive calibration process was undertaken. This included calibrating for gas volume, and flow rates at high, medium, and low levels, as well as for air, oxygen, and carbon dioxide gases. Metabolic simulators were also calibrated to ensure the accuracy and reliability of the test results (30). Throughout the CPET, a 12-lead electrocardiogram and pulse oximetry were continuously monitored to kinetically track cardiac and respiratory function. Blood pressure measurements were taken at two-minute intervals using an automated cuff. The exercise protocol began with a 3-minute resting phase, followed by a 3-minute warm-up involving no-power exercise at a rate of 55–65 revolutions per minute (r/min). Completion of symptom-restricted maximal extreme exercise was in accordance with the standards of the continuous incremental power protocol set by the Harbor-UCLA Medical Center (31). The patient’s disease history, height, weight, and exercise habits were considered and set at an appropriate incremental rate of 10–35 W/min to ensure that symptom-limited maximal exercise was achieved within 6–15 minutes of exercise duration (12,31). A 5-minute recovery period concluded the protocol (12). Throughout the CPET, subjects were encouraged and closely monitored by a physician or technician, ensuring both motivation and safety during the testing process.

CPET reference parameters

In our study, a range of exercise and cardiopulmonary parameters were assessed during CPET for both heart failure patients and NS. CPET data were analyzed using the principles of clinical trial standardization at Harbor-UCLA Medical Center (32). Parameters such as V˙O2, heart rate (HR), V˙O2/HR, peak respiratory exchange ratio (RER), peak systolic blood pressure (SBP), peak diastolic blood pressure (DBP), minute ventilation (V˙E), V˙E/V˙CO2, oxygen uptake efficiency (OUE), tidal volume (V˙T), partial pressure of end-tidal carbon dioxide (PETCO₂), and partial pressure of end-tidal oxygen (PETO₂) were indirectly measured or calculated. The AT was determined using the V-slope method (32,33). V˙E/V˙CO2 slope, derived from (Y = a + bx) linear regression analyses of the V˙E and V˙CO2 data throughout the exercise (32). The lowest V˙E/V˙CO2 was determined by selecting the 90-second lowest average (32). The OUE plateau (OUEP), represented by V˙O2/V˙E maximum, was defined as the 90-second largest average (32).

Furthermore, we analyzed changes in nine key parameters at various stages of the CPET, namely rest, warm-up, AT, peak, and recovery phases. The data processing methods for the different exercise phases were consistent with the study by Sun et al. (32). (I) The Rest phase is calculated as the average of the last 120s of data. (II) The warm-up phase is derived from the average of the last 30s of data. (III) Similarly, the peak phase is based on the average of the last 30s of data. (IV) AT phase, the oxygen consumption value primarily relies on the 10s measurement. The PETCO₂ and the V˙E/V˙CO2 are averaged over the AT point and the subsequent 60s. Conversely, the PETO₂ and the OUE reflect the average of the AT point and the data from the previous 60s. (V) The Recovery phase is predominantly expressed as the 10s measurement taken at 1 or 2 minutes into recovery. This comprehensive approach allowed us to capture a detailed physiological profile of the exercise response in heart failure patients compared to NS.

Determination of OB and R-LShunt by gas test parameters of CPET

OB and R-LShunt were first diagnosed by three experienced researchers and then reviewed by a CPET expert to ensure accuracy and authenticity of the results. To determine the presence of OB and R-LShunt during exercise, they analyzed the parameter changes in the CPET 9-panel plot using the following criteria. Confirmation of OB during CPET was conducted in accordance with established criteria: (I) the amplitude of cyclic fluctuations was ≥30% of the mean value over the same period, with each fluctuation lasting between 40 and 140 seconds, and V˙E exhibited at least three consecutive cyclic fluctuations; (II) at least two additional CPET parameters, aside from V˙E (such as V˙O2, V˙CO2, V˙E/V˙CO2, RER, HR, V˙O2/HR, PETO₂, and PETCO₂), also demonstrated similar cyclic fluctuations (18). According to the parameters mentioned above, we refer to an atypical OB tendency when the V˙E respiratory amplitude is less than 30% (but ≥25%), the cycle of fluctuations is less than three (but ≥2), and there are ≥2 CPET parameters with the aforesaid periodic fluctuations.

Criteria for R-LShunt identification include: (I) an abrupt and sustained increase in PETO₂, RER, and V˙E/V˙CO2 after exercise; and (II) a sudden or continuous decrease in PETCO₂, V˙O2/V˙E, and peripheral oxygen saturation (SpO₂) (11).

Echocardiography

All heart failure patients underwent echocardiography within 2 weeks of hospitalization. Left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), and tricuspid regurgitation peak gradient (TRPG) were determined according to the consensus document of the European Association of Cardiovascular Imaging (34,35).

Right heart catheterization

Right heart catheterization was performed in patients with RHF within 2 weeks after CPET and according to the methodology described by the American College of Cardiology (ACC) expert consensus (36,37). Systolic pulmonary artery pressure (sPAP), diastolic pulmonary artery pressure (dPAP), mean pulmonary artery pressure (mPAP), and pulmonary artery wedge pressure (PAWP) were measured. CO and CI were measured by the Fick method.

Identification of subgroups

In the LHF group, patients were further categorized based on the presence or absence of OB, resulting in two subgroups: one with OB (72 subjects, 59%) and another without OB (51 subjects). Similarly, the RHF group was divided based on the presence or absence of R-LShunt due to PH. This division led to two subgroups: one with R-LShunt (64 subjects, 63%) and another without R-LShunt (37 subjects). The study then compares the similarities and differences between the groups with LHF and RHF, as well as the respective subgroups.

Statistical analysis

Statistical analyses in this study were conducted using SPSS software, version 26.0 (IBM Corporation, Armonk, NY, USA). We presented continuous variables either as mean ± standard deviation (SD) (minimum–maximum) or as median (25^th, 75^th percentile). Categorical variables were expressed in terms of percentages. To compare continuous variables, we employed a one-way analysis of variance (ANOVA) or the t-test for variables with a normal distribution. For those variables that did not follow a normal distribution, the Kruskal-Wallis test was used. For the comparison of categorical variables, we utilized the Chi-squared test, based on the appropriateness of the dataset. In our analysis, a P value of less than 0.05 was set as the threshold for statistical significance. This criterion was applied to determine the significance of differences observed in the variables across the groups under study.

Results

Baseline clinical characteristics of patients with LHF and RHF

The baseline clinical characteristics of patients with LHF and RHF are detailed in Table 1. The age and body mass index (BMI) of LHF and RHF patients were similar (P=0.47 and 0.07, respectively). Notably, patients with LHF had higher spirometry results than those with RHF (P=0.047). Additionally, a higher proportion of women was observed in the RHF patient group (P<0.001). Regarding maximum voluntary ventilation (MVV), the data indicated no significant difference between the LHF and RHF groups (P=0.08), suggesting similar rest ventilatory capacity in both conditions. We found that TRPG was significantly lower in LHF patients (30.75±11.58 mmHg) than in RHF patients (61.67±23.13 mmHg) (P<0.001). However, LHF patients were characterized by larger LAD, increased LVEDD, higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and lower ejection fractions, indicative of more pronounced cardiac structural changes and dysfunction (all P<0.001).

Characterization of LHF and RHF in CPET

A significant finding in the study was the presence of OB in 59% of the LHF patients. In contrast, 63% of RHF patients exhibited an R-LShunt. Particularly in patients with PH, an increase in right atrial pressure during exercise can lead to the opening of the foramen ovale, resulting in R-LShunt. However, we identified R-LShunt in 28 (23%) patients with LHF (27 with OB and one without OB). and the one patient without OB was evaluated by three physicians and diagnosed as possibly having R-LShunt due to the lack of a characteristic presentation. Twenty of the LHF patients had a TRPG of more than 40 mmHg. On the other hand, nine R-LShunt patients and eight non-R-LShunt patients out of the 17 (17%) RHF patients had OB, but the eight non-R-LShunt patients had atypical OB. Merely two patients who were diagnosed with standard OB and had RHF also had R-LShunt. From this, we can see that lower incidence of R-LShunt in patients with LHF and of OB in patients with RHF. These findings highlight distinct pathophysiological features in LHF and RHF, with implications for their management and treatment.

CPET core parameters outcomes

Table 2 describes the differences in CPET parameters across patients with LHF, RHF, and NS. A notable observation is the significantly lower peak V˙O2 as a percentage of predicted (%pred) in both LHF and RHF patients compared to NS, with all P<0.001. In a detailed comparison between LHF and RHF patients, it was observed that LHF patients exhibited lower values in several key parameters: peak V˙O2 (%pred), peak HR, AT (%pred), the lowest V˙E/V˙CO2 (%pred), and V˙E/V˙CO2 slope, with respective P values of 0.008, <0.001, 0.01, 0.001, and 0.02. On the other hand, parameters such as peak V˙O2/HR and OUEP (%pred) were significantly higher in LHF patients compared to those with RHF (both P<0.001). The remaining CPET parameters did not show notable differences between the LHF and RHF groups. For a comprehensive understanding of these variations and similarities in CPET parameters among LHF, RHF, and NS groups, please refer to the detailed data presented in Table 2.

Table 3 presents a comprehensive analysis of CPET parameters, echocardiographic findings, hemodynamic profiles, and NT-proBNP levels across various groups. A key observation was that peak V˙O2 (%pred) was significantly lower in the OB group compared to no OB group, with P<0.001. Further detailed analysis revealed in Table 3 shows that the OB group had higher NT-proBNP levels and lower ejection fractions compared to no OB group, with all differences being statistically significant (all P<0.001). Similarly, peak V˙O2 (%pred) was notably lower in the R-LShunt group compared to no R-LShunt group (all P=0.001). Table 3 also illustrates that NT-proBNP levels, pulmonary artery systolic pressure, and mPAP were all significantly higher in the R-LShunt group than in the no R-LShunt group (P<0.001, 0.007, and 0.03, respectively). Additionally, the CI was found to be lower in the R-LShunt group compared to the no R-LShunt group (P=0.04).

Table 3 also provides a detailed comparison of CPET parameters among different subgroups of patients with LHF and RHF. In the LHF category, the subgroup with OB exhibited significantly lower values in several key exercise parameters compared to the no OB subgroup. Specifically, peak HR, AT (%pred), peak V˙O2/HR (%pred), and OUEP (%pred) were all lower in the OB group (P=0.005, <0.001, <0.001, <0.001, respectively). Furthermore, the lowest V˙E/V˙CO2 and V˙E/V˙CO2 slope was significantly higher in the OB group (all P<0.001), indicating poorer exercise tolerance and gas exchange efficiency in this subgroup. Similarly, in the RHF category, the subgroup with an R-LShunt demonstrated lower values in AT (%pred), peak V˙O2/HR (%pred), and OUEP (%pred) compared to the no R-LShunt subgroup (P=0.01, 0.002, <0.001, respectively). In addition, the lowest V˙E/V˙CO2 and V˙E/V˙CO2 slope were significantly higher in the R-LShunt group (all P<0.001), suggesting reduced exercise capacity and efficiency in gas exchange. For further details on how other CPET parameters compared between the two LHF subgroups and the two RHF subgroups, Table 3 provides comprehensive intergroup comparison data.

Variations in key parameters at rest, warm-up, AT, peak, and recovery during CPET

Figure 1A-1I presents a comprehensive visual representation of the changes in nine CPET parameters from rest through to the end of unloaded exercise among LHF patients, RHF patients, and NS. A notable observation is the behavior of the PETCO₂. In NS, PETCO₂ showed a significant increase from the rest phase to the AT phase. In contrast, this increase was less pronounced in the heart failure groups, particularly in RHF patients who exhibited persistently low PETCO₂ values throughout the exercise. During the CPET, HR was consistently lower (all P<0.001), while O₂ pulse and PETCO₂ were significantly higher (all P<0.001) in the LHF group compared to the RHF group. Furthermore, OUE was markedly lower (all P<0.001), the PETO₂ (all P<0.001) and the V˙E/V˙CO2 (P=0.001, 0.01, 0.008, <0.001, respectively) were higher in RHF patients compared to LHF patients, from the warm-up phase through to recovery. This indicates greater ventilatory inefficiency in RHF patients. The dynamics of the remaining CPET parameters throughout the exercise stages are detailed in Figure 1A-1I, providing a nuanced understanding of the cardiopulmonary response patterns in these patient groups.

Figure 1 Groups differences in key parameters among the NS and patients with LHF or RHF during CPET. (A) HR increased gradually from rest to the peak period, followed by a gradual decline. Notably, patients with LHF exhibited a poorer HR response to exercise. (B) significantly increased with exercise duration after AT; however, was comparable between LHF and RHF patients during the peak period. (C) V˙T displayed a similar trend to V˙E. (D) V˙O2 was significantly lower in both LHF and RHF patients compared to NS throughout the exercise period. (E) OUE rose gradually from rest to AT and then declined significantly thereafter; however, patients with RHF demonstrated lower OUE during the AT period. (F) Both LHF and RHF patients exhibited persistently high values of V˙E/V˙CO2. (G) The V˙O2/HR increased and then decreased with exercise duration across all three groups, although V˙O2/HR was lower in patients with RHF during the peak phase. (H) PETO₂ in all three groups decreased to the AT phase before rising with exercise duration, while PETO₂ in RHF patients remained consistently high. (I) PETCO₂ values were consistently low in RHF patients. The kinetics of changes in nine parameters among the three groups, the mean ± SD of nine parameters in LHF, RHF, and NS groups at different stages of exercise: rest, warmup, AT, peak, and recovery, are shown in (A-I). Data among the groups were compared using one-way ANOVA. *, P<0.05, LHF group versus NS group. ^#, P<0.05, LHF group versus RHF group. ^&, P<0.05, RHF group versus NS group. ANOVA, analysis of variance; AT, anaerobic threshold; CPET, cardiopulmonary exercise testing; HR, heart rate; LHF, left heart failure; NS, normal subjects; OUE, oxygen uptake efficiency; PETCO₂, partial pressure of end-tidal carbon dioxide; PETO₂, partial pressure of end-tidal oxygen; Rec., recovery; RHF, right heart failure; SD, standard deviation; V˙E, minute ventilation; V˙E/V˙CO2, carbon dioxide ventilatory efficiency; V˙CO2, oxygen uptake; V˙O2/HR, oxygen pulse; V˙T, tidal volume.

Figure 2A-2I provides a detailed graphical interpretation of the variations in nine CPET parameters throughout the exercise phases among the OB, no OB, and NS groups. A significant observation from the AT phase to the Recovery phase is that the ventilatory function parameters, namely V˙E and V˙T, were substantially lower in both OB and no OB subgroups of LHF patients compared to NS (all P<0.001). Interestingly, there was no marked difference between the OB and no OB groups in these parameters. From the Rest phase to the Peak exercise phase, several disparities emerged in the OB group compared to both the no OB group and NS. The PETCO₂ and the OUE were consistently lower in the OB group (all P<0.001). Concurrently, the V˙E/V˙CO2 was significantly higher (all P<0.001) in the OB group. Additionally, the PETO₂ was also higher in the OB group compared to both the no OB group (P=0.02, 0.006, <0.001, <0.001, respectively) and NS (P=0.001, <0.001, <0.001, <0.001, respectively).

Figure 2 Group differences in key parameters among no OB, OB, and NS groups during CPET. (A) Both the OB and no OB groups exhibited a weak HR response to exercise, with peak HR being relatively lower in OB patients. (B) V˙E at peak exercise was comparable between the OB and no OB groups; however, both were significantly lower than that of the NS group. (C) V˙T demonstrated a similar trend to V˙E. (D) The peak phase V˙CO2 was lowest among OB patients. (E) OUE increased gradually from rest to AT but then decreased significantly; notably, the increasing trend was less pronounced in OB patients, with OUE being even lower during the AT period. (F) PETO2 was significantly higher in the OB group compared to the no OB group throughout the entire process. (G) The V˙O2/HR ratio was significantly lower in both the OB and no OB groups than in the NS group, with the peak-period OB group exhibiting the lowest V˙O2/HR. (H) V˙E/V˙CO2 in the OB group displayed consistently high values during CPET. (I) PETCO₂ remained consistently low in the OB group. The kinetics of changes in nine parameters among three groups, the mean ± SD of nine parameters in no OB, OB, and NS groups at different stages of exercise: rest, warmup, AT, peak, and recovery, are shown in (A-I). Data among the groups were compared using one-way ANOVA. *, P<0.05, no OB group versus NS group. ^#, P<0.05, no OB group versus OB group. ^&, P<0.05, OB group versus NS group. ANOVA, analysis of variance; AT, anaerobic threshold; CPET, cardiopulmonary exercise testing; HR, heart rate; NS, normal subjects; OB, oscillatory breathing; OUE, oxygen uptake efficiency; PETCO₂, partial pressure of end-tidal carbon dioxide; PETO₂, partial pressure of end-tidal oxygen; Rec., recovery; SD, standard deviation; V˙E, minute ventilation; V˙E/V˙CO2, carbon dioxide ventilatory efficiency; V˙O2, oxygen uptake; V˙O2/HR, oxygen pulse; V˙T, tidal volume.

Figure 3A-3I provides a comprehensive summary of the changes observed in nine CPET parameters during exercise for the R-LShunt, the no R-LShunt, and NS groups. A notable observation is that during the peak exercise period, both V˙E and V˙T were significantly lower in the R-LShunt and no R-LShunt groups compared to NS (all P<0.001). In NS, the PETCO₂ showed a notable increase from rest to the AT phase, followed by a dramatic decrease from AT to recovery. However, in the no R-LShunt group, both the rise and fall of PETCO₂ were less pronounced. Interestingly, the R-LShunt group tended to an almost continuous decrease in PETCO₂ levels throughout the exercise. PETCO₂ (all P<0.001) and OUE (P<0.001, <0.001, <0.001, <0.001, 0.02, respectively) were consistently lower in the R-LShunt group compared to the no R-LShunt group during CPET. Additionally, the PETO₂ (P<0.001, <0.001, <0.001, <0.001, 0.004, respectively) and the ratio of V˙E/V˙CO2 (all P<0.001) were significantly higher in the R-LShunt group compared to the no R-LShunt group during the entire exercise session.

Figure 3 Group differences in key parameters among no R-LShunt, R-LShunt, and NS groups during CPET. (A) HR was significantly lower in both R-LShunt and no R-LShunt patients compared to NS group; however, no significant difference was observed between R-LShunt and no R-LShunt groups. (B) V˙E increased initially and then decreased with exercise duration, but there was no difference in peak values between R-LShunt and no R-LShunt groups. (C) V˙T exhibited a pattern similar to that of V˙E. (D) V˙O2 Peak in R-LShunt group was lower than in the other groups. (E) OUE in R-LShunt group remained relatively constant and significantly lower than the other two groups prior to AT, subsequently decreasing to lower values. (F) PETO₂ in R-LShunt group remained consistently high before AT, then increased to higher levels, and was significantly greater than that of the other two groups throughout CPET. (G) V˙O2/HR in the peak R-LShunt group was significantly lower compared to the other two groups. (H) The V˙E/V˙CO2 ratio was consistently high in the R-LShunt group during CPET. (I) PETCO₂ was consistently low in R-LShunt group during CPET. The kinetics of changes in nine parameters among three groups, the mean ± SD of nine parameters in no R-LShunt, R-LShunt, and NS groups at different stages of exercise: rest, unloaded, AT, peak, and recovery, are shown in (A-I). Data among the groups were compared using one-way ANOVA. *, P<0.05, no R-LShunt group versus NS group. ^#, P<0.05, no R-LShunt group versus R-LShunt group. ^&, P<0.05, R-LShunt group versus NS group. ANOVA, analysis of variance; AT, anaerobic threshold; CPET, cardiopulmonary exercise testing; HR, heart rate; NS, normal subjects; OUE, oxygen uptake efficiency; PETCO₂, partial pressure of end-tidal carbon dioxide; PETO₂, partial pressure of end-tidal oxygen; R-LShunt, right-to-left shunting; Rec., recovery; SD, standard deviation; V˙E, minute ventilation; V˙E/V˙CO2, carbon dioxide ventilatory efficiency; V˙CO2, oxygen uptake; V˙O2/HR, oxygen pulse; V˙T, tidal volume.

Discussion

Mechanisms of pathophysiology in OB patients

The HIPM approach postulates a sophisticated respiratory regulation mechanism. According to this model, blood carrying wave-like respiratory signals travels through the pulmonary veins, left atrium, and left ventricle, and is then ejected into the aorta and carotid arteries. This blood acts on peripheral chemoreceptors and subsequently influences the respiratory center via upstream nerves, ultimately affecting inhalation and inspiration processes. Concurrently, this blood flow reaches the cerebral capillaries, crosses the blood-brain barrier, and acts on central chemoreceptors within the cerebrospinal fluid. This action directly modulates the sensitivity of the respiratory integrating center, thereby maintaining respiratory stability and forming the core loop of integrated regulation (1). Increased circulation time from the lungs to the brain and chemoreceptors resulted from reduced CO, leading to delayed information transfer (38). Concurrently, both central and peripheral chemoreceptors exhibit heightened sensitivity to the partial pressures of oxygen and carbon dioxide (38). In patients with LHF, this integrated respiratory regulation is often compromised. The heart’s inadequate ejection capacity fails to meet peripheral tissue perfusion needs, leading to compensatory increases in left atrial, pulmonary venous, and capillary pressures, as well as increased resistance in the pulmonary circulation. This results in chronic pulmonary stasis believed to contribute to respiratory abnormalities in LHF patients (39).

Our study corroborates these insights, revealing that OB was present in 59% of LHF patients, aligning with findings from other studies. In addition, OB was found in 17% of the RHF patients; however, only two of these patients had typical OB. This could be because severe RHF eventually impairs left heart function as well, which can result in anomalies related to breathing. The categorization of LHF and RHF in this research was only dependent on the kind of heart failure resulting from the underlying ailment. The absence of post-total heart failure grouping studies permits additional investigation into the factors that predict complete heart failure. For instance, Sun and colleagues reported OB in approximately 50% of 508 LHF patients. Furthermore, they identified OB, combined with peak V˙O2 and lowest V˙E/V˙CO2, as the best predictors of early mortality and morbidity in these patients (18). This highlights the significance of understanding respiratory regulation in LHF, emphasizing the need for integrated approaches to predict and manage the condition effectively.

In our study, patients with LHF were classified into two distinct groups based on the presence or absence of OB, following the diagnostic criteria outlined by Sun et al. (18). At the same time, we also include atypical OB in the OB group. Our recording parameters for the rest and warm-up phases were limited to a total of 3 minutes. This time constraint affects the calculation of the number of OB fluctuation cycles. Furthermore, for patients with severe heart failure, reaching the AT during the warm-up period is detrimental to the confirmation of OB. Although atypical OB do not fully meet the criteria for confirming standard OB, they still exhibit tendencies characteristic of OB. Therefore, we have included atypical OB in the OB group. This distinction allowed for a comparative analysis of CPET performance between these two subsets of patients. Our observations revealed that patients in the OB group exhibited lower values in several key CPET parameters. These included shorter CPET duration, lower peak HR, peak SBP, peak workload, peak V˙O2, AT, peak V˙O2/HR, and OUEP. Conversely, these patients displayed higher values for the lowest V˙E/V˙CO2 and V˙E/V˙CO2 slope, indicating reduced efficiency in gas exchange. Furthermore, during the exercise from rest to peak, the OB group showed lower PETCO₂ and OUE, and higher values for the V˙E/V˙CO2 and PETO₂. These findings suggest that the OB group experiences more pronounced challenges in motility and gas exchange during exercise. The outcomes of our study align with previous research, which indicates that LHF patients with OB exhibit more severely impaired cardiac function, both at rest and during exercise (26). This consistency underscores the significance of identifying OB in LHF patients, as it is indicative of more severe cardiac dysfunction and exercise intolerance.

Our findings indicate that the incidence of OB in patients with LHF is higher than that observed in patients with RHF. Therefore, the impact of LHF on the respiratory system is more pronounced than that of RHF. Additionally, the overall functional status of patients with OB is significantly worse compared to those without OB, suggesting that the presence of OB is indicative of more severe disease progression.

Pathophysiological mechanisms in R-LShunt

Under the theory of HIPM, the right heart is conceptualized as playing a crucial role in an integrally regulated bypass circulation. This process involves venous return entering the right atrium, passing through the right ventricle, and proceeding into the pulmonary circulation, thereby influencing subsequent breaths and affecting gas exchange in the lungs (1). In our study, all RHF patients exhibited PH, a condition that, when prolonged, leads to RV hypertrophy and increased right atrial pressure. A critical observation during CPET was that when right atrial pressure exceeded left atrial pressure, the patent foramen ovale, resulted in an R-LShunt.

Notably, we detected the presence of R-LShunt in 63% of the RHF patients during CPET. Since patients with LHF will eventually progress to total heart failure, we found that R-LShunt occurred in 23% of patients with LHF. The majority of patients with LHF in this group are more severe and have OB, which is a significant manifestation of advanced heart failure. In LHF patients, 28 cases showed R-Lshunt, while 20 patients with LHF had a TRPG greater than 40 mmHg. Among these, seven patients demonstrated both R-Lshunt and TRPG >40 mmHg, suggesting a potential progression toward total heart failure. In the 13 patients who had TRPG >40 mmHg without developing R-Lshunt, TRPG values were near the cutoff, which may have contributed to the absence of R-Lshunt. For the remaining 21 patients who only exhibited R-Lshunt, since R-Lshunt may occur during the end stage of exercise, and Echocardiographic examinations are conducted while the subject is at rest, the incidence of R-Lshunt diagnosed through CPET may be higher than that identified by echocardiographic. Consequently, our study highlights the significant role of CPET in identifying R-Lshunt during the end stage of exercise. This approach enhances our understanding of disease progression and early intervention, and we believe it holds substantial promise for further exploration in future studies.

The incidence of R-LShunt in our study was relatively higher than what has been reported in other research. This difference could be attributed to the specific characteristics of our study sample. All participants were inpatients at Fu Wai Hospital and typically presented with more severe disease states. Consequently, this led to a higher incidence of R-LShunt among our patient cohort. These findings underscore the significant impact of severe PH and its progression on the right heart function, particularly in the context of RHF. The high prevalence of R-LShunt observed in our study highlights the critical need to consider these pathophysiological aspects in the management and treatment of RHF patients.

In our study, we categorized RHF patients into two groups: those with the R-LShunt group and those without the R-LShunt group. We observed that exercise tolerance and gas exchange parameters, including peak V˙O2, peak V˙O2/HR, and OUEP, were markedly reduced in the R-LShunt group compared to the no R-LShunt group. Additionally, V˙E markers such as V˙E/V˙CO2 and the lowest V˙E/V˙CO2 ratio were higher in the R-LShunt group. Throughout the entire exercise session, both the PETCO₂ and V˙E/V˙CO2 displayed abnormal trends in the R-LShunt group when compared to the no R-LShunt group and NS. The R-LShunt group also exhibited lower PETCO₂ and OUE, higher PETO₂, and an increased V˙E/V˙CO2 ratio throughout the exercise. The underlying causes of these observations can be attributed to several factors. Firstly, the R-LShunt allows deoxygenated blood, high in CO₂ and H⁺, to bypass the lungs and enter systemic circulation. This triggers the carotid chemoreceptors to increase ventilation, resulting in heightened dead space ventilation and altered gas exchange patterns (20). This triggers the carotid chemoreceptors to increase ventilation, resulting in heightened dead space ventilation and altered gas exchange patterns. Secondly, prolonged PH and pulmonary vasculopathy or occlusion contribute to a ventilation-perfusion mismatch, leading to increased ineffective ventilation and the observed changes in PETCO₂ and OUE (10). Furthermore, the R-LShunt group demonstrated higher levels of NT-proBNP and mPAP, along with a lower CI compared to the no R-LShunt group. These findings align with previous studies suggesting that these parameters are critical in prognosticating heart failure outcomes (40,41). Overall, our results suggest that patients in the R-LShunt group exhibit abnormal gas exchange patterns, reduced exercise capacity and V˙E, more severe disease manifestation, and potentially poorer prognoses compared to those in the no R-LShunt group.

Pathophysiological mechanisms of LHF and RHF

Our study revealed that patients with LHF and RHF exhibit significantly poorer overall function compared to NS. In particular, exercise tolerance was markedly more limited in LHF patients, while RHF patients demonstrated greater impairment in gas exchange capacity. Key findings from the incremental exercise phase of CPET indicated that, compared to RHF patients, those with LHF had lower peak HR, AT, peak V˙O2, lowest V˙E/V˙CO2, and V˙E/V˙CO2 slope. Conversely, LHF patients exhibited higher peak V˙O2/HR and OUEP. Additionally, throughout the CPET, the PETCO₂ was consistently lower in RHF patients than in LHF patients. In contrast, PETO₂ and V˙E/V˙CO2 were significantly higher in RHF patients, particularly from the warm-up to the peak phase of incremental exercise. Echocardiographic measurements also revealed that LHF patients have larger left atrial internal diameters, increased left ventricular end-diastolic volumes, higher levels of NT-proBNP, and lower ejection fractions. These findings collectively suggest a more severe disease profile, weaker exercise capacity in LHF patients, and a more compromised gas exchange capacity in RHF patients.

Peak V˙O2 stands out as a pivotal parameter for measuring endurance or exercise capability, reflecting the maximal rate of oxygen transport and utilization (42). Its significance extends beyond assessing physical capacity. Peak V˙O2 is instrumental in predicting prognosis and determining the optimal timing for heart transplantation in heart failure patients (16,43). Our study’s findings diverge from those of Liu et al., who reported more severe dyskinesia at peak exercise in RHF patients compared to LHF patients (44), In our research, we observed a different trend: patients with LHF had lower V˙O2 than those with RHF. This may be due to the relatively mild disease of the RHF patients in our study. During exercise, LHF patients often face challenges with sufficient CO and skeletal muscle perfusion. This inefficiency can lead to early-onset fatigue (45), forcing premature termination of exercise and resulting in lower peak V˙O2 readings. Thus, our study indicates that the diminished exercise capacity in LHF patients is primarily due to their hearts’ inability to meet the increased physiological demands during exercise. This underscores the critical role of CO and skeletal muscle perfusion in determining exercise tolerance in LHF patients.

V˙O2/HR, representing the oxygen consumption required by the heart for each beat, serves as an indicator of stroke volume (46). Our study found that peak V˙O2/HR was notably lower in patients with RHF compared to those with LHF. Several factors contribute to this observation: A significant majority (93%) of LHF patients in our study were on β-blocker medication. β-blockers are known to limit HR during exercise, which in turn influences the V˙O2/HR ratio (47). This HR limitation due to β-blockers is likely a key factor contributing to the differing peak V˙O2/HR values between LHF and RHF patients. In our heart failure cohorts, there was no significant difference in Peak V˙O2/HR (%pred) between the LHF and RHF groups. This finding might be attributed to the higher proportion of women in the RHF group, who typically have a lower peak V˙O2/HR ratio. During exercise, RHF patients experience an increase in pulmonary vascular resistance. When right atrial pressure surpasses left atrial pressure, blood is diverted through the foramen ovale, creating an exercise-induced R-LShunt. This R-LShunt allows deoxygenated blood to mix with arterial blood, leading to reduced oxygen content and consequently, a decrease in the V˙O2/HR ratio. These results highlight the complexity of cardiovascular responses in heart failure, particularly in RHF patients where the interplay of increased pulmonary resistance and R-LShunt mechanisms contributes to the reduced efficiency in oxygen utilization per heartbeat.

V˙E/V˙CO2, a key parameter measured during CPET, indicates the efficiency of CO₂ clearance from the lungs during exercise, reflecting the adequacy of pulmonary ventilation relative to perfusion (42,48). Similarly, V˙E/V˙CO2 and OUEP are critical in assessing overall cardiovascular function, particularly in terms of oxygenation and oxygen transport (49). Our study revealed that patients with RHF exhibited higher values of lowest V˙E/V˙CO2, V˙E/V˙CO2 slope, and lower OUEP. Additionally, the V˙E/V˙CO2 was found to be elevated during the entire exercise session, from warm-up through recovery, in RHF patients. This pattern suggests a more severe ventilation-perfusion mismatch and ineffective ventilation in RHF compared to LHF. PETO₂ at rest and during exercise was observed to be higher in RHF patients than in LHF patients. Conversely, PETCO₂ was significantly lower in RHF patients, indicating an altered gas exchange dynamic in these individuals. Parameters such as V˙E/V˙CO2, lowest V˙E/V˙CO2, V˙E/V˙CO2 slope, OUE, OUEP, PETO₂, and PETCO₂ are commonly used to evaluate gas exchange efficiency. These measures are also crucial for diagnostic and prognostic purposes in clinical settings (42,50). The trends observed in these CPET parameters for RHF patients point to a diminished gas exchange capacity during exercise, highlighting a more pronounced ventilation-blood flow mismatch, ineffective ventilation, and compromised exercise cardiorespiratory fitness.

Study limitations

This study has several limitations. (I) The study was a retrospective, single-center, small sample, and potentially biased statistically. (II) Lack of gold standard for detection of OB and R-LShunt for validation. The determination of the OB and R-LShunt relies on the variations observed in each parameter across the nine plots of the CPET. However, the absence of objective quantitative criteria means that subjective assessments by researchers may influence the incidence rate. (III) Patients with RHF who had R-LShunt during exercise were judged only on the basis of CPET and post-exercise echocardiography was not performed. (IV) Our outcome assessment did not employ a blinded methodology. However, our diagnosis of CPET remains unaffected by clinical diagnoses. We analyze the pathophysiological phenomena related to respiration, circulation, and metabolism based on the changes observed in CPET parameters. (V) There were differences in gender and age between the NS group and the two heart failure groups. Larger, multicenter, prospective studies are therefore required to demonstrate the reliability of the results.

Conclusions

During CPET, both LHF and RHF patients exhibited significant overall dysfunction. However, distinct differences were noted between the two groups. LHF patients displayed poorer exercise tolerance, which can be attributed to reduced CO, insufficient skeletal muscle perfusion, and more severe disease progression. In contrast, while RHF patients showed a relatively small decrease in exercise tolerance, they had worse gas exchange capacity. This impairment in RHF is due to a mismatch between ventilation and perfusion during exercise, an increase in dead space volume, and a reduced ability of the lungs to adapt during exertion. Furthermore, the presence of OB in LHF patients and R-LShunt in RHF patients was associated with more pronounced functional limitations compared to those without these conditions. This suggests that specific pathophysiological mechanisms in LHF and RHF contribute differently to exercise capacity and gas exchange efficiency, resulting in varying degrees of exercise limitation.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease, for the series “Holistic Integrative Physiology Medicine and Health: from Theory to Clinical Practice”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-519/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-519/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-519/prf

Funding: This work was supported by the National Key Research and Development Program of China (Nos. 2022YFC2010000 and 2022YFC2010003), the National Key Research and Development Program of China (No. 2022YFC3601000), the National Key Research and Development Program of China (Nos. 2020YFC2009002 and 2020YFC2009006), the National Natural Science Foundation of China (No. 81470204), the Fuwai Hospital, National Cardiovascular Institute of Chinese Academy of Medical Sciences (No. 2012-YJR02), the National Hi-Tech Research and Development Program (863 Program) (No. 2012AA021009), the Research on Clinical Characteristics of the Capital (No. Z141107002514084), the Research and Outcome Promotion of Clinical Characteristics in the Capital (No. Z161100000516127), the Foreign Experts Project of State Administration of Foreign Experts (Nos. 2015, 2016, T2017025, T2018046, and G2019001660), and the Peking Union Medical College Teaching Reform Program (No. 2018E-JG07).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-519/coif). The series “Holistic Integrative Physiology Medicine and Health: from Theory to Clinical Practice” was commissioned by the editorial office without any funding or sponsorship. X.G.S. served as an unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The retrospective study was approved by the Ethics Committee of Fuwai Hospital (No. 2023-2236). Individual consent was waived due to the retrospective nature of this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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