Cardiopulmonary Exercise and Respiratory Function Testing and Their Association with Mortality and Heart Transplantation in Patients with Heart Failure ()
1. Introduction
Cardiopulmonary exercise testing (CPET) has emerged as a valuable tool for predicting prognosis in heart failure (HF) patients and offers insights that guide decisions related to heart transplantation. Among the well-established CPET variables, peak oxygen uptake (VO2), ventilatory efficiency (expressed as the slope of VE/VCO2), and peak work rate (W) have demonstrated significant predictive value [1]. Current guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA) acknowledge the importance of these variables in risk assessment for heart failure patients [2]. Existing literature lacks comprehensive studies that retrospectively analyze CPET variables in patients who have definitively undergone heart transplantation.
Despite the recognized significance of VO2, VE/VCO2 slope, and peak work rate, our investigation explored whether additional CPET variables could offer further insight into prognosis and transplantation probability. We sought to address this gap by analyzing CPET variables in a broad heart failure population, providing a more comprehensive perspective on mortality risk. We aimed to identify and compare additional variables associated with mortality and transplantation for heart failure patients.
2. Methods
2.1. Patients
This was a single-center retrospective study of patients with stable chronic heart failure who routinely underwent annual CPET to assess functional capacity and determine candidacy for heart transplantation. The study period was from December 2020 through January 2023. Patients were identified from a larger group of individuals initially referred for evaluation of exertional dyspnea and fatigue. The investigation was approved as an exempt study by the institutional review board of the University of Southern California Health Sciences Center (HS-21-00017). As policy, in our laboratory all patients are asked to study and sign a consent form prior to any CPET, including those conducted for routine clinical purposes. Heart failure was identified according to the consensus statement published by Bozkurt et al. [3]. Patients with pneumonia, acute heart and/or respiratory failure, cancer, COVID-19 infection, and chronic respiratory disorders such as obstructive airway, interstitial lung and neuromuscular diseases were excluded from analysis.
During the analysis, we did not separate patients with heart failure with reduced ejection fraction from those with preserved ejection fraction because there were fewer patients in the latter group. For the purpose of this study, we grouped all heart failure patients together and categorized them by mortality status and whether they received heart transplants or not (Figure 1). All testing was completed before any heart transplants took place.
2.2. Lung Function Testing
Spirometry was performed in the seated position according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines [4]. Reference values for FVC and FEV1 were from Crapo et al. [5].
2.3. Cardiopulmonary Exercise Testing
These studies incorporated the following details: 1) clinical and anthropometric characteristics of patients; 2) adherence to international guidelines for methods of CPET [6]; and 3) the safety of CPET, defined as reported adverse events. The CPETs were performed before any heart transplants took place.
The exercise testing equipment consisted of a stationary cycle ergometer (Med Graphics CPX Ultima system, Medical Graphics Corporation, St. Paul, MN) that was calibrated before and after each test. The mechanical dead space volume, depending on the mouthpiece and connections used, ranged from 45 to 65 mL for this system. Calibration of gas concentrations using primary standard gases and flow was performed using a 3 L syringe prior to each test. Patients were asked not to exercise on the day of the test and to refrain from consuming caffeinated beverages four hours before the test. Following the explanation of each procedure, informed consent was obtained under witness. Prior to beginning the test, subjects were familiarized with the stationary cycle ergometer and mouthpiece and cycled on the ergometer for approximately 10 minutes. They were seated and breathed through a mouthpiece with a nose clip in place. After a minimum of five minutes of resting measurements, they were exercised on the ergometer with increasing workloads at increments of 5 - 15 Watts, based on patients’ tolerability, using the Godfrey protocol [7]. Data collection continued for several minutes post-exercise for gas collection and electrocardiogram monitoring purposes.
The following variables were recorded every 15 seconds: minute ventilation (V’E), inspired oxygen concentration (FiO2), end-tidal oxygen tension (PetO2), inspired oxygen uptake (VO2), and end-tidal carbon dioxide output (PetCO2). Peak VO2 was expressed as the highest 30-second average value recorded during the last stage of the exercise test [8]. Anaerobic threshold (AT) was determined by the V-slope method [9]. Heart rate and rhythm were monitored continuously throughout the study with the 12-lead ECG. In addition, the following variables were derived from the data: tidal volume (Vt), respiratory rate, minute ventilation Ve/maximum voluntary ventilation (Ve/MVV), respiratory exchange ratio (RER), O2/pulse (VO2/HR), and ventilatory equivalents for carbon dioxide and oxygen (Ve/VCO2 and Ve/VO2, respectively). Peak VO2 was determined as the highest 20- to 30-second average achieved during exercise and expressed as ml/kg/min. The Ve/VCO2 slope was computed using least squares linear regression fitting of breath-by-breath values recorded throughout the whole exercise [8]. Normal values for these variables were derived from Sun et al. [9]. Ve/VCO2 was also corrected for VO2 (Ve/VCO2/VO2) [10]. The chronotropic index (CI) was calculated by dividing the difference between maximal and resting heart rate (in beats/min) by the difference between maximal and resting oxygen uptake (in L/min). Predicted values for CI were computed as follows:
CI = 106.9 + (0.16 × age) + (14.3 × sex) - (0.31 × height) - (0.24 × weight) [11].
All patients with VO2max (expressed in mL/min) less than 84% predicted were considered as having functional limitation of cardiovascular, pulmonary vascular, or ventilatory limitation [12] ATS Statement on CPX]. Patients with a Ve/MVV of greater than 75% predicted were considered to have a reduced ventilatory reserve. An O2/pulse of less than 80% predicted represented a reduced stroke volume related to circulatory limitation [13]. No patients experienced any adverse events during testing.
Patients who showed either ventilatory or circulatory limitation were classified based on predominant CPET features; if, for example, they exhibited resting tachycardia (heart rate > 90 beats/min), a normal Ve/MVV (<75%), a decreased O2/pulse (<80% predicted), and ventilatory equivalents that were increased (>30) and/or failed to decrease with exercise, they were classified as having a circulatory deficit. The slope and intercept for Ve/VCO2 were computed for all patients according to the relationship y = a + bx, where y was the difference between Ve at rest and peak exercise, x was the difference between VCO2 at rest and peak exercise, a was the intercept and b was the slope [9]. The oxygen uptake efficiency slope (OUES) was derived from the relationship of VO2 to the logarithm of Ve during exercise: VO2 = a log 10 Ve + b, where “a” is the OUES and “b” is the intercept [14].
2.4. Statistical Analysis
Descriptive data are shown as mean and standard deviation. Normality of the data was confirmed using the Shapiro-Wilk test. Comparisons among cohorts were conducted by multivariate analysis of variance (ANOVA), using the Bonferroni correction to account for the large number of compared variables. Associations between physiologic variables were determined by Pearson’s correlation, expressed as r2. A p-value of <0.05 was considered statistically significant for intergroup comparisons and for inter-variable associations.
3. Results
3.1. Patient Characteristics
Of 350 patients who underwent evaluation for exertional dyspnea and were screened for heart failure, 166 were diagnosed with heart failure related to structural heart disease (Figure 1). The remaining patients (n = 184) had primary diagnoses of various forms of respiratory disorders or idiopathic pulmonary hypertension. Their overall mean age and standard deviation (±SD) was 52 ± 15.6 years with a distribution of 128 males and 38 females (Table 1). Their mean body mass index (BMI) was 25.9 ± 2.5 kg/m2. Eighty (48%) patients were former smokers (more than 2 years previously); none were current smokers. Beta-blockers were used among 75% of study participants. The severity of cardiac dysfunction was classified as New York Heart Association Severity II and III. In 97 patients for whom echocardiographic data were available, the mean (±SD) left ventricular ejection fraction (LVEF) was 38 ± 17%; eighty percent of patients exhibited a reduced ejection fraction (<40%). We found no significant differences in the LVEF among survivors and expired patients, nor among those who underwent heart transplant versus those who did not (Table 2 and Table 3). Seventeen percent of patients were diagnosed with ischemic etiology of heart failure, while 75% were diagnosed with non-ischemic dilated cardiomyopathy. Twenty-eight patients (17%) expired by the end of data collection. Eighteen patients (11%) underwent heart transplantation. Two (11%) of the transplanted and 26 (18%) of the non-transplanted patients expired during the study.
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Figure 1. Flow chart describing the study cohort.
Table 1. Anthropometric and physiological data of 166 patients.
Age (y) |
52 ± 15.6 |
Sex (M/F) |
128/38 |
BMI (kg/m2) |
29.5 ± 5.9 |
Beta-blocker use (%) |
75 |
LVEF (%) |
38.4 ± 17 |
Etiologies: |
|
Ischemic (%) |
17 |
Non-ischemic dilated cardiomyopathy (%) |
75 |
Hypertrophic cardiomyopathy (%) |
4 |
Congenital (%) |
4 |
Reduced ejection fraction (%) |
80 |
Preserved ejection fraction (%) |
20 |
FVC (L) |
3.5 ± 1.1 |
FVC (% predicted) |
82 ± 18 |
FEV1 (L) |
2.7 ± 0.9 |
FEV1 (% predicted) |
81 ± 19 |
FEV1/FVC (%) |
78 ± 11 |
Vemax/MVV (%) |
46 ± 14 |
RER |
1.19 ± 0.09 |
VO2max (mL/kg/min) |
15.5 ± 15.9 |
VO2max (% predicted) |
54.7 ± 16.8 |
VO2 at anaerobic threshold (mL/kg/min) |
10.7 ± 3.6 |
VCO2max (mL/kg/min) |
19.9 ± 8.7 |
Ve/VCO2 slope |
37.1 ± 14.2 |
Ve/VCO2 intercept (L/min) |
1.7 ± 3 |
Ve/VCO2/VO2 |
2.4 ± 1 |
ΔVO2/ΔWork (mL/kg/min/Watt) |
11.3 ± 0.9 |
Chronotropic index (/L) |
30.3 ± 3.6 |
OUES (mL/min/L/min) |
1320 ± 535 |
PetCO2, rest (mm Hg) |
32.5 ± 5.3 |
PetCO2, peak (mm Hg) |
31.7 ± 5.5 |
Values are mean ± SD. Abbreviations: BMI, body mass index; LVEF, left ventricular ejection fraction; FVC, forced vital capacity; FEV1, forced expiratory volume in one second; Ve, minute ventilation; MVV, maximum voluntary ventilation; RER, respiratory exchange ratio; VO2, oxygen output; VCO2, carbon dioxide output; AT, anaerobic threshold; OUES, oxygen uptake efficiency slope; PetCO2, end-tidal carbon dioxide tension; PetO2, end-tidal oxygen tension.
Table 2. Physiologic variables in expired and living patients.
|
Expired |
Living |
p |
n |
28 |
138 |
----- |
LVEF (%) |
33.5 ± 16 |
39.5 ± 17 |
0.1 |
FVC (L) |
2.9 ± 0.9 |
3.6 ± 1.2 |
<0.001 |
FVC (% predicted) |
71.9 ± 18.8 |
85.3 ± 16.9 |
<0.001 |
FEV1 (L) |
2.3 ± 0.7 |
2.8 ± 0.9 |
0.002 |
FEV1 (% predicted) |
73 ± 19 |
83 ± 18 |
0.001 |
FEV1/FVC (%) |
77 ± 15 |
78 ± 9 |
0.7 |
Vemax/MVV |
0.46 ± 0.13 |
0.46 ± 0.14 |
0.83 |
RER |
3.2 ± 0.2 |
3.2 ± 0.1 |
0.64 |
VO2max (mL/kg/min) |
12 ± 3.8 |
16.5 ± 6 |
<0.001 |
VO2max (% predicted) |
45.5 ± 14.6 |
57.5 ± 16.5 |
<0.001 |
VO2 at AT (mL/kg/min) |
8.6 ± 2.3 |
11.2 ± 3.7 |
<0.001 |
VCO2max (mL/kg/min) |
15.2 ± 6.8 |
21.3 ± 8.7 |
<0.001 |
Ve/VCO2 slope |
42.4 ± 10.9 |
35.5 ± 14.8 |
0.01 |
Ve/VCO2 intercept (L/min) |
0.9 ± 2.5 |
1.8 ± 3.4 |
0.16 |
Ve/VCO2/VO2 |
3.5 ± 1.2 |
2.2 ± 0.7 |
0.005 |
Ve/VO2max |
51.6 ± 14.6 |
44.3 ± 10.8 |
0.001 |
Ve/VO2 at AT |
38.7 ± 7.9 |
34.5 ± 13.9 |
0.078 |
ΔVO2/ΔWork (mL/kg/min/Watt) |
11.9 ± 11.6 |
11.1 ± 8.3 |
0.62 |
Chronotropic index (/L) |
34.4 ± 47.5 |
29.3 ± 32 |
0.43 |
O2/pulse, max |
8.6 ± 3.2 |
10.4 ± 3.3 |
0.02 |
OUES (mL/min/L/min) |
1,049 ± 511 |
1,394 ± 530 |
<0.001 |
PetCO2, rest (mm Hg) |
32.3 ± 4.9 |
32.6 ± 5.4 |
0.71 |
PetCO2, peak (mm Hg) |
29.8 ± 6.1 |
32.3 ± 5.2 |
0.01 |
Values are mean ± SD. Abbreviations are the same as in Table 1.
Table 3. Physiologic variables in transplanted (obtained pre-transplant) and non-transplanted patients.
|
Pre-transplant |
Non-transplanted |
p |
n |
18 |
148 |
----- |
LVEF (%) |
31.6 ± 16.8 |
39.3 ± 17 |
0.09 |
FVC (L) |
3.1 ± 0.8 |
3.5 ± 1.2 |
0.12 |
FVC (% predicted) |
74.7 ± 13.9 |
83.1 ± 18.5 |
0.07 |
FEV1 (L) |
2.3 ± 0.6 |
2.8 ± 0.9 |
0.033 |
FEV1 (% predicted) |
70 ± 15 |
82.3 ± 18.8 |
0.011 |
FEV1/FVC (%) |
74.5 ± 33.3 |
77.9 ± 30.4 |
0.21 |
Vemax/MVV |
0.46 ± 0.13 |
0.46 ± 0.14 |
0.83 |
RER |
1.2 ± 0.2 |
1.2 ± 0.1 |
0.3 |
VO2max (mL/kg/min) |
11.4 ± 2.4 |
15.9 ± 5.9 |
0.002 |
VO2max (% predicted) |
40.8 ± 9.6 |
56.4 ± 16.8 |
<0.001 |
VO2 at AT (mL/kg/min) |
8.2 ± 2.3 |
10.9 ± 3.6 |
0.001 |
VCO2max (mL/kg/min) |
13.4 ± 3.3 |
20.6 ± 8.9 |
0.001 |
Ve/VCO2 slope |
42.9 ± 11.1 |
36.4 ± 14.4 |
0.02 |
Ve/VCO2 intercept (L/min) |
0.5 ± 2.4 |
1.7 ± 3.2 |
0.14 |
Ve/VCO2/VO2 |
3.8 ± 1 |
2.3 ± 0.6 |
0.001 |
Ve/VO2max |
50.2 ± 30.8 |
45.5 ± 12.2 |
0.13 |
Ve/VO2 at AT |
40.1 ± 14.3 |
34.9 ± 12.7 |
0.12 |
ΔVO2/ΔWork (mL/kg/min/Watt) |
9.7 ± 3.6 |
11.5 ± 9.3 |
0.45 |
Chronotropic index (/L) |
53.6 ± 63.7 |
27.6 ± 30.9 |
0.005 |
O2/pulse, max |
8.6 ± 2.2 |
10.1 ± 3.2 |
0.06 |
OUES (mL/min/L/min) |
912 ± 295 |
1364 ± 537 |
<0.001 |
PetCO2, resting (mm Hg) |
33.4 ± 5.1 |
32.6 ± 5.3 |
0.35 |
PetCO2, peak (mm Hg) |
28.3 ± 5.6 |
32.1 ± 5.3 |
0.007 |
Values are mean ± SD. Abbreviations are the same as in Table 1.
3.2. Expired and Living Patients
Table 2 compares expired and living patients based on cardiopulmonary exercise testing (CPET) results. Expired patients had 19% lower forced vital capacity (FVC) and 18% lower forced expiratory volume in one second (FEV1) compared to living patients (p < 0.001 and p = 0.002, respectively). However, there were no significant differences among % predicted FVC, FEV1/FVC, and Ve/VCO2 intercept values.
Concerning exercise capacity, expired patients exhibited 27% lower VO2 max (p < 0.01), 20.7% lower VO2max % predicted (p < 0.001), and 23% lower values in VO2 at AT (p < 0.001) compared to living patients. Deceased patients also exhibited a 29% lower VCO2 max (p < 0.001), 14% higher peak Ve/VCO2 (p = 0.003), 59% higher Ve/VCO2/O2 (p = 0.005), and 19% higher Ve/VCO2 slope (p = 0.009). The deceased group had a 17% lower O2/pulse than the surviving group (p = 0.02). The oxygen uptake efficiency slope (OUES) was 25% lower in the deceased group (p < 0.001). While PetCO2 at rest showed no significant difference among subgroups (p = 0.71), expired patients exhibited a PetCO2 at peak exercise that was 7.7% less than in living patients (p = 0.01). No statistically significant differences were found between expired and living patients for Ve/VCO2 at AT, Ve/VO2 at AT, and ΔVO2/ΔWork.
3.3. Transplanted versus Non-Transplanted Patients
Table 3 compares physiologic variables in patients who were eventually transplanted with those who were not. Patients who underwent transplantation exhibited 18% lower FEV1 (L) values compared to those who did not receive a transplant (p = 0.033). No statistically significant differences were found between the two groups for FVC, FVC % predicted, FEV1/FVC, Ve/VCO2 intercept, and Ve/VO2 at AT.
With respect to cardiopulmonary exercise capacity, the to-be transplanted group exhibited a VO2 max that was 28% less than that of the non-transplant group (p = 0.002). Similarly, the VO2 at anaerobic threshold (VO2 at AT) was 25% lower in the transplant group than in the non-transplanted group (p = 0.003). Additionally, the transplant group demonstrated a 35% lower value in peak carbon dioxide production (VCO2 max) compared to the non-transplanted group (p = 0.001). Ve/VCO2/VO2 in the expired group was 65% higher than in living patients (p = 0.001).
Transplanted patients exhibited an oxygen uptake efficiency slope (OUES) that was 33% lower (p < 0.001) than in the non-transplanted group. While PetCO2 at rest exhibited no significant differences (p = 0.35), the transplant group demonstrated a relative decrease in PetCO2 at peak exercise, 11% lower (p = 0.007) than in the non-transplanted group. Transplanted patients exhibited a chronotropic index that was 94% higher than those who did not undergo transplant (p = 0.005), indicating a notable decrease in heart rate response during exercise. This difference was not observed between deceased and living patients. The O2/pulse in the to-be transplanted group was 15% less than in the non-transplanted group, a non-significant difference (p = 0.06).
4. Discussion
4.1. General Findings
Our findings highlight differences in exercise capacity, gas exchange, and circulatory response associated with heart transplantation compared to patients who did not receive a transplant. Key findings in deceased and transplanted patients (recorded prior to transplant) included reduced lung function, VO2max, O2/pulse, OUES, and increased Ve/VCO2max and Ve/VO2 as compared to living and non-transplanted patients, respectively.
The chronotropic index among deceased patients and in those who later underwent heart transplant was increased as compared to survivors and patients who did not undergo transplant. The index considers age, resting heart rate, and functional capacity and is independent of the stage of exercise or the protocol used [15] [16]. After adjusting for a number of demographic and physiological factors, Robbins et al. [17] found that a high Ve/VCO2 and a low chronotropic index remained independent predictors of death due to any cause. Others have described the Ve/VCO2 slope as a key determinant of mortality [8] [18]-[22]. Lin et al. [23] found that patients with heart failure and with an OUES < 1.3 and Ve/VCO2 > 38 exhibited a higher risk for cardiac events, particularly those with COPD. We also found lower mean OUES values in patients who underwent transplant, indicating a higher degree of dead space breathing contributing to the decrease in cardiopulmonary reserve. In this connection, the peak PetCO2 in patients who underwent transplant was reduced, a reflection of the inability of cardiac output to keep up with ventilation, resulting in the overall ventilation/perfusion ratio exceeding 1.
Chronotropic incompetence may be considered a major limiting factor in the exercise capacity of patients with heart failure. It is an important cause of exercise intolerance and an independent predictor of adverse cardiovascular events and mortality [24]. Although the underlying mechanisms for chronotropic incompetence in HF are not fully understood, the imbalance of the autonomic nervous system that is shifted toward the sympathetic pathway decreases β-adrenergic responsiveness, resulting in a reduced heart rate response to exercise [25]. Witte et al. [26] found a linear correlation between change in HR and peak VO2. CI may be considered a limiting factor in the exercise capacity of patients with HF, but it has not been a consistent finding. In a study of 195 patients, of whom 90 had severe left ventricular systolic dysfunction, Jamil et al. [27] showed that increasing heart rate in unselected patients with heart failure did not improve exercise tolerance or improve symptoms, and conversely, that lowering HR did not worsen exercise tolerance or exercise-related symptoms. There has been a lack of a standardized approach to diagnosing the disease, further complicated by changes in HR dynamics in the HF population, which render reference values derived from a normal population invalid.
4.2. Expired versus Living Patients
Deceased patients exhibited lower O2/pulse, OUES, VO2max, VO2 at AT, VCO2max, and PETCO2 at peak exercise, and higher VE/VCO2max and VE/VCO2 slope (as well corrected for VO2) compared to living patients. The mean Ve/VCO2 in our deceased patients is virtually the same as that reported by Sarullo et al. (41.8) [18]. In general, our findings align with those of Brawner’s study [1], suggesting that even when cardiac transplantation is removed as an endpoint, these values still exhibit a high association with heart failure prognosis.
The difference in the O2/pulse between deceased and surviving patients indicate a similar predictive feature of outcome [1] [10].
We found that the OUES in surviving patients was 1.05 L/min/L/min and, on average, 33% higher than in individuals who expired. Guazzi et al. [10] reported an OUES cutoff of 1.05 for high-risk cardiac outcomes, similar to the findings of Lin et al. [23] who reported a threshold of 1.3. OUES is influenced by the onset of lactic acid production and therefore incorporates circulatory, ventilatory, and musculoskeletal function. The log transformation of Ve creates high linearity in relation to VO2 [14], thus making the OUES theoretically effort-independent, enabling its calculation also in the case of a submaximal CPET. Yet, OUES has not been considered a necessary variable to be described in a CPET report. In a study of over 2000 patients with heart failure with reduced ejection fraction, Gordon et al. [28] concluded that while OUES was associated with clinical outcomes independent of the VE/VCO2 slope, its prognostic utility was inferior to that of peak VO2, even when measured at submaximal effort.
Deceased patients exhibited a mean Ve/VCO2/VO2 of 3.5, 59% higher than in surviving individuals. Using multivariate analysis, Guazzi et al. [10] showed that the Ve/VCO2/VO2 index retained a prognostic power greater than that of both VE/VCO2 slope and peak VO2. A Ve/VCO2/VO2 ≥2.4 indicated a higher risk for cardiac mortality.
The mean CI among deceased patients was 17% higher than in survivors (34.4/L vs 29.3/L), although this was not a statistically significant difference due to variability. An increase in the CI has been associated with decreased exercise tolerance and worse outcomes in individuals with heart failure [11]. Spiro et al. [29] have suggested reference values for CI for healthy men (42 - 43/L) and women (63 - 71/L). Given that 77% of our subjects were men, a mean CI of 53.6/L is well above the normal range (for men). This finding indicates a steep relationship between change in heart rate vs change in VO2 from rest to peak exercise and is typical in patients with heart failure, ischemic heart disease and valvular heart disease, severe deconditioning and certain myopathies [11].
Deceased patients had lower values for FVC and FEV1. These findings can be attributed to several factors associated with heart failure, including pulmonary congestion, pleural effusion, and/or respiratory muscle weakness.
4.3. Transplanted versus Non-Transplanted Patients
Overall, transplanted patients showed significantly lower FEV1 values, peak VO2max, VO2 at AT, and VCO2 max compared to non-transplanted individuals. Our findings are similar to those of Mancini et al. [30] who reported that patients listed for heart transplant were more likely to have a VO2max < 14 ml/kg/min. Our study’s VO2max range of 11.4 to 15.9 ml/kg/min aligns with this observation. Similarly, Garcia Bras et al. [31] identified a Ve/VCO2 slope closer to 40 as indicative of a higher likelihood of transplantation. Our study aligns with this observation and deviates slightly from the traditional Ve/VCO2 slope of 35 as defined by the ACC/AHA guidelines [2]. There has been controversy over how the slope is computed; we computed the Ve/VCO2 slope from the very beginning to the end of the Ve vs VCO2 plot, which results in a higher value than when computing the slope from the beginning up to the respiratory compensation point (RT), as the slope increases from RT to VO2max [22] [32]-[36]. The overall slope also has a greater association with mortality [8] [9] [22] [33] [36] [37].
Of the ventilatory equivalents, only Ve/VCO2 discriminated between transplanted and non-transplanted patients. The finding that Ve/VO2 did not may be related to less variability in Ve/VCO2 than Ve/VO2 during moderate intensity exercise because of the sensitivity of ventilatory control to PaCO2 and pH in the physiologic ranges [9] [32]. Transplanted patients may also have reduced sensitivity to blood chemical changes from renal and neural effects of immunosuppressive agents. In addition, the OUES in patients who eventually underwent heart transplantation was, on average, 35% lower than in those who did not undergo transplant (p < 0.001), findings similar to those of Guazzi et al. [10] and Lin et al. [23], and predictive of worse clinical outcomes (had they not undergone transplant). In addition, patients who eventually underwent heart transplant exhibited a CI that was 94% greater (p < 0.005) than those who did not undergo transplant, with similar implications regarding their potential outcomes.
5. Strengths and Limitations
Our study has strengths: We describe changes in chronotropic index, OUES, and Ve/VCO2/VO2 amongst survivors and transplanted patients, supporting a handful of other investigations [10] [22]-[28]. Other findings were similar to prior studies regarding VO2max and VE/VCO2 max and its slope [1], which adds to the validity of our data. In addition, we also describe differences in the chronotropic index amongst cohorts not previously reported.
Our study also has limitations. This was a single-center retrospective study with a relatively small cohort of patients with advanced heart failure. Its retrospective nature may introduce selection and information biases. However, the changes in commonly used variables of CPET in survivors and deceased patients were similar to those of others described. Second, we did not include as covariates beta-blocker dose, device therapy or other medications; many patients were receiving combinations of medications whose timing and dose changed over time. Third, there was also a preponderance of male subjects that limits generalizability of findings to both sexes. Finally, a larger population study may reveal additional significant differences among cohorts.
We pooled patients with both reduced and preserved EF when performing the comparisons amongst subgroups in part because of uneven numbers of the subgroups. In any case, we found no statistically significant differences in LVEF between patients with HFpEF and those with HFrEF across studied variables. In addition, recent studies have shown that individuals with HFpEF have similar outcomes as those with HFrEF [37]-[40]. Shah et al. [38] found in a 5-year outcomes study that risk-adjusted analyses exhibited a similar mortality and rehospitalization for both HFrEF and HFpEF. Their findings were similar to results from the JCARE-CARD study [39], which showed that patients with HFpEF had a mortality risk and re-hospitalization rate similar to those with HFrEF. In addition, Triposkiadis et al. [40], when adjusting for risk factors, found that among patients hospitalized with HF, there was no mortality difference among patients with reduced and preserved EF.
6. Conclusions
Our findings confirm the potential utility of specific cardiopulmonary exercise testing (CPET) variables in informing prognostic assessments and aiding in the identification of suitable candidates for heart transplantation in the context of heart failure management. In general, the differences in variables among deceased and living patients reflect similar differences between patients eventually undergoing heart transplant and those who did not. The addition to the analysis of the chronotropic index, OUES, and Ve/VCO2/VO2 further highlights metabolic differences among cohorts.