3. Exercise Parameters of Increased Importance in CHF Patients

Cardiac output is usually normal at rest in patients with mild HF, but it does not increase with physical activity ^[16]. The peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ in HF is directly related to peak cardiac output and perfusion of exercising muscles. The failure to increase cardiac output decreases perfusion to these muscles and can cause anaerobic metabolism at lower workloads and muscle fatigue. Cardiopulmonary exercise testing provides an important and objective method for determining the functional capacity of patients with CHF. There are several variables in addition to $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ that have prognostic implications in HF that can only be measured using the CPET. During CPET, peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ and the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ slope during exercise are important parameters used to measure functional capacity and have prognostic value.

3.1. $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/CO₂ Slope

In chronic HF, minute ventilation ( $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E) for a given level of carbon dioxide production ( $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂) might be abnormally high during exercise due to increased dead space ventilation, decreased lung compliance, increased chemo- and metabolic reflex sensitivity, early metabolic acidosis, and abnormal pulmonary hemodynamics. The relationship between $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E and $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂, in L/min, represents the matching of ventilation and perfusion within the pulmonary system, and a ratio < 30 is considered normal. The explanation for this analysis is that higher ratios indicate that a higher minute ventilation is needed to excrete CO₂, which reflects inefficiency in the system. The $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ slope is a continuous variable that predicted major cardiac events in a study with 448 patients with chronic HF (both HFrEF and HFpEF); a very poor prognosis occurred in patients with a slope ≥45 ^[17].

3.2. Peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂

This parameter is considered as a universal prognostic marker. The $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ is the amount of oxygen being used by the tissues per minute, and the peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ represents the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ at the peak of exercise. There are three measured units in CPET reports: the absolute peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ is measured in mL O₂/min, the relative peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ in mL O₂/kg/min/, or the predicted peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ in %, based on the study by Neder et al., which used anthropometric characteristics to create predicted peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ tables ^[18].

3.3. Respiratory Equivalent Ratio (RER) and Anaerobic Threshold

Defined as the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ ratio, a normal RER value is usually between 0.7 and 1.0, with a low level (0.7) indicating fat metabolism and a high level (1.0) indicating carbohydrate metabolism, and ratios in between indicating mixed fuel consumption. As exercise increases to higher intensities, $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ exceeds $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂, increasing the ratio. Currently, this ratio is the best non-invasive indicator of exercise effort, and a peak value ≥1.10 is considered an excellent exercise effort ^[19]. The principle behind this analysis is based on the classic pathways of aerobic and anaerobic glycolysis in which the CO₂ produced during the anaerobic glycolysis is higher than in aerobic metabolism, reflecting a less-efficient system of producing energy. The anaerobic threshold represents the point of exercise at which the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ increases exponentially relative to the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂. 

3.4. Partial Pressure of End-Tidal Carbon Dioxide (PETCO₂) in mmHg at Rest and during Exercise

The end-tidal carbon dioxide level reflects the matching of ventilation and perfusion in the pulmonary and cardiac systems. Therefore, it reflects disease severity in a number of clinical disorders, including HF, pulmonary hypertension, COPD, and interstitial lung disease.

3.5. Exercise Oscillatory Ventilation

Periodic breathing is a form of irregular breathing characterized by a regular cyclic variation in ventilation with increases and decreases in tidal volume interrupted by pauses with a cycle length of approximately 1 min. Periodic breathing, or Cheyne and Stokes respiration in the resting state, has been recognized as a characteristic of HF for over 200 years. This breathing pattern can also occur during exercise and is called exercise oscillatory ventilation (EOV). This develops in a significant percentage of HF patients ^[19].

4. Protocols and Graded Exercise Testing

Different exercise testing protocols have been described in the literature. This equipment, including both cycle ergometers and treadmills, can measure the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ max, $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂, and $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E. Generic types of protocols include progressive, incremental, and multistage (every 3 min, with a “pseudo” steady-state metabolic level at each stage) protocols ^[20]. In clinical practice, maximal incremental protocols are often used. Changes in $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂, $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂, and $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E often lag behind changes in work rate. Therefore, the preferred protocol should increase the work rate at a constant rate.

4.1. Important Exercise Protocol Characteristics

Exercise time should be maintained between 6 and 12 min, which is probably the optimal time to obtain efficient and useful metabolic and functional information. Both ergometer and treadmill protocols should be preceded by an initial warm-up phase at 0 Watts for 1–3 min and should include a recovery phase of at least 5 min with a tapering workload.

4.2. Gas Analysis Systems

Respiratory gas exchange measurement is a crucial part of the CPET technique; maximal oxygen uptake and anaerobic threshold determination serve as indices of exercise capacity that can be applied to various clinical problems, such as differential diagnosis of exertional dyspnea and fatigue, in which maximal oxygen uptake and anaerobic threshold determination are combined with a simultaneous assessment of circulatory and ventilatory reserves. Arterial blood gas determination can be used to define ventilation–perfusion relationships. During exercise, both components of the Fick equation (cardiac output [CO] and arteriovenous O₂ difference [(A-V) O₂]) should increase; the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ max is the maximum amount of O₂ that can be used for metabolic work for a given form of exercise and is related to the maximum CO and (A-V) O₂ that can be attained ^[21].

5. Interpretation of CPET Parameters

5.1. Target Exercise Load for CPET

The most important benefit of the use of a bike ergometer instead of a treadmill is the linear increase in workload. With a treadmill, it is possible to change slope and speed, but not the workload itself, and therefore it is almost impossible to generate a linear increase in workload that provides an accurate objective measurement of the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂/work rate relationship. The exercise ramp protocol should have an exercise duration of ~10 min with an interval ranging from 8 to 12 min ^[22]. This means that the workload should be adjusted for each patient to achieve this test duration.

5.2. Exercise Limits in Uncomplicated Medical Disorders

Cardiac disorders: Patients with cardiac disorders usually meet their exercise limit when they reach their predicted maximum heart rate. This typically occurs at a lower work level and lower $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ max. They often cross an anaerobic threshold at a lower work rate, and they have higher $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ slopes. Pulmonary disorders: These patients reach their maximum exercise capacity when they reach their ventilatory limit. The respiratory pattern includes higher respiratory rates and lower tidal volumes that do not increase during exercise. They may desaturate during exercise. Muscular disorders: These patients often stop exercise because of muscle fatigue and have not reached either a cardiac or respiratory limit. Depending on the exact metabolic abnormality in these muscles, these patients may or may not have increased anaerobic metabolism.

6. Risk Stratification in HF Using CPET

6.1. Prognostic Value of CPET Parameters

Careful measurement of ventilation and O2 uptake patterns in HF can quantify disease severity and prognosis. Cardiopulmonary exercise testing is routinely used in the prognostic evaluation of patients with HF with reduced ejection fractions (HFrEF), especially when advanced therapies are considered. The first study evaluating the prognostic utility of CPET parameters dates back to 1991, when Mancini et al. published their groundbreaking work on the predictive value of peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂, and established a peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ cutoff of <14 mL/kg/min as a criterion for which 1-year survival was significantly lower (47%) than survival with transplantation (70%) ^[23]. In contrast, individuals with a peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ > 14 mL/kg/min had a higher (95%) 1-year survival, suggesting that cardiac transplantation could be safely deferred in ambulatory patients with severe left ventricular dysfunction and a peak exercise $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ of more than 14 mL/kg/min. Following these results, studies have focused on ventilatory efficiency during CPET, expressed as the minute ventilation per carbon dioxide production ( $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂) slope, and have demonstrated that it is a robust prognostic marker in patients with HFrEF ^{[24][25][26][27]}. Risk predictions of hospitalization and/or death is important for both patients and physicians. For patients, this information can help them understand the severity of their illness and thereby guide patients in decision making, including preferences for advanced HF therapies and/or end-of-life care. For physicians, these predictions provide guidance toward which treatment to offer patients, and when to offer treatment. Interpretation of cardiopulmonary exercise testing in the individual patient should start with an assessment of whether maximal effort was achieved or not, as indicated by RER ^[25]. A RER >1.0 to 1.1 indicates maximal patient physiological effort. A heart rate >85% of predict also correlates with maximum physiological effort but is often not achieved in patients on beta blockers and/or with chronotropic incompetence.

6.2. CPET Studies in Patients with Heart Failure with Preserved Ejection Fractions

Nadruz et al. studied the clinical characteristics, CPET results, and outcomes in 195 patients with heart failure with preserved ejection fractions (>50%), 144 patients with heart failure with mid-range ejection fractions (40–49%), and 630 heart failure patients with reduced ejection fractions (<40%) ^[28]. There were significant differences in the clinical characteristics among these three groups. Ho et al. analyzed clinical information, exercise testing results, and outcomes in 461 patients with left ventricular ejection fractions ≥50% and New York Heart Association Class II–IV symptoms ^[29][30]. These patients frequently had comorbid diseases, including hypertension, obesity, diabetes, and atrial fibrillation. The patients were placed in separate categories using criteria established by the American College of Cardiology/American Heart Association (ACC/AHA), the European Society of Cardiology (ESC), and the Heart Failure Society of America (HFSA). The use of three different criteria resulted in significant differences in the number of patients classified as HFpEF. The peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ max ranged from 16.2 ± 5.2 mL/kg/min in patients classified by ACC/AHA criteria to 12.7 ± 3.1 mL/kg/min in those classified by HFCA criteria. Patients in all three classification groups had elevated $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ slopes. 

7. Cardiopulmonary Exercise Testing and Drug Trials

When patients are classified according to their peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂, patients with a peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ less than 12 mL/kg/min had a reduced diffusion capacity, a reduced membrane component of diffusion, a reduced vital capacity, and a reduced alveolar volume. This indicates that pulmonary function tests can identify important changes in pulmonary function in patients with chronic HF and potentially help explain changes in their exercise capacity ^[30][31]. Patients treated with angiotensin-converting enzyme (ACE) inhibitors have a significant increase in lung diffusion, exercise tolerance, and peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂, a decrease in peak dead space/tidal volume ratio, and a decrease in the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ slope.  Studies with carvedilol indicate that it does not affect pulmonary mechanics or exercise capacity. Neither peak workload nor $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ improved with the drug. However, quality-of-life scores did improve, and there were reduced ventilatory responses to exercise, demonstrated by a decrease in the $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ E/ $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ CO₂ slope. Patients on carvedilol had a significant decrease in diffusion capacity, which was explained by a reduction in membrane conductance. The diffusion capacity on carvedilol was significantly lower than the diffusion capacity in patients treated with bisoprolol or nebivolol. 

8. Biomarkers, Cardiopulmonary Exercise Testing, and Cardiac Rehabilitation

Kruger et al. prospectively studied 70 patients with chronic HF who underwent symptom-limited bicycle exercise testing ^[32]. The mean age of these patients was 60.3 ± 10.4; the mean ejection fraction was 26.4 ± 6.0%. There was a significant negative correlation between BNP concentration and peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂, $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ at the anaerobic threshold, the relationship between minute ventilation and CO₂ production, the number of Watts reached during exercise, and the left ventricular ejection fraction. BNP levels could discriminate between patients who had a peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ less than 10 mL/kg/min or a peak $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ less than 14 mL/kg/min. These authors suggest that BNP may be an effective way to monitor therapy and exercise programs in patients with HF. MicroRNA (miRNAs) are non-coding RNAs that help regulate gene expression by inhibiting transcription. The interaction of miRNAs with their target genes depends on the intracellular location of miRNAs, the concentration of the miRNAs and target mRNAs, and the degree of binding of the miRNA to mRNA. These microRNA levels have been studied in patients with chronic HF participating in cardiac rehabilitation. Witvrouwen et al. compared plasma miRNA levels in 25 patients with heart failure enrolled in a 15-week combined aerobic and strength exercise program with 21 sedentary males to determine the effect of exercise ^[33]. These investigators measured miR-23a, miR-140, miR-146a, miR-191, and miR-210 levels, which are associated with pathways relevant to exercise adaptation, in both patient groups.  In HF patients with reduced ejection fractions, capillary density in skeletal muscle is reduced. Both miR-23 and miR-146a stimulate angiogenesis; therefore, reduced miR-23a and miR-146A levels after 15 weeks of training may reflect increased capillary density and a reduced need for angiogenesis. In addition, HF patients with reduced ejection fractions and reduced physical activity levels often have skeletal muscle wasting, and this contributes to fatigue during daily activities and reduces $\stackrel{}{\mathrm{V}\stackrel{}{\dot{}}}$ O₂ peak during CPET. Both miR-23 and miR146a limit skeletal muscle atrophy by inhibiting the ubiquitin–proteasome pathway and Wnt family member 11 expression, and increased levels of these miRNAs suggest that the patient is having adaptive responses in skeletal muscle to prevent wasting. In conclusion, exercise effects the levels of miRNAs involved in pathways related to exercise adaptation, which may help improve skeletal muscle and the angiogenic response to exercise in HFrEF patients. The study also demonstrates that measuring miRNAs may help classify patients into phenotypes, monitor responses to treatment, especially exercise rehabilitation, and possibly understand the pathogenesis of muscle dysfunction in HF patients ^{[33][34][35][36]}.