Cardiopulmonary Exercise Testing: Adjunctive and Practical Applications

For selected patients it may be important to directly measure aerobic capacity or cardiorespiratory fitness (CRF) using ventilatory gas exchange responses via an automated metabolic measurement system. This methodology is commonly referred to as cardiopulmonary exercise testing (CPX), which may be particularly applicable to the following patient subsets: assessment of CRF, expressed as the peak or maximal oxygen consumption (VO2peak or VO2max), and/or in risk-stratifying patients with heart failure (HF) who may be considered for heart transplantation; clarifying the functional impact and severity of valvular heart disease; differentiation of cardiac versus pulmonary limitations as a cause of exertional dyspnea or impaired CRF; and evaluation of exercise capacity more precisely due to the inaccuracies associated with estimating VO_2peak or VO_2max from the attained work rate. In reality, many sedentary healthy adults and cardiac patients are unable to demonstrate a leveling off of oxygen consumption with increasing workloads. Most achieve a level of fatigue and discomfort far below their physiologic maximum, precluding the attainment of a “true” VO_2max. This is why fatigue or symptom-limited peak performance, or VO_2peak, may differ from the physiologic VO_2max.

The CPX is essentially a conventional peak or sign/symptom-limited exercise test that is complemented by simultaneous gas exchange measurements, including oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory rate, tidal volume, minute ventilation (VE), oxygen pulse, respiratory exchange ratio (RER; VCO2/VO2), and the ventilatory-derived anaerobic threshold (V-AT), which signifies the break point in linearity when VCO2 is plotted as a function of VO2, expressed as a percentage of the VO2max. This method has been reported to be a sensitive, reliable, noninvasive technique for the detection of the onset of metabolic acidosis,1 which signifies the highest submaximal exercise intensity that may be sustained without inducing an appreciable increase in blood lactate. Exercise tolerance or, more specifically CRF, expressed as mL O2/kg/min or as metabolic equivalents (METs; 1 MET = 3.5 mL O2/kg/min), is one of the strongest and most consistent prognostic markers in persons with and without coronary disease.2 Because the VE/VCO2slope, an index of ventilatory efficiency, may be helpful in detecting elevated pulmonary pressures,3 often a consequence of left-sided valvular heart disease,4 or decompensated HF or mortality in patients with severe aortic stenosis and preserved ejection fraction,5 it has been suggested as a marker of the severity of HF and appears to provide prognostic information that is independent from, and superior to, the highest VO2 attained (VO2peak) during CPX.6 Finally, two additional cardiopulmonary variables have been reported to improve the sensitivity of CPX, suggesting exercise-induced myocardial ischemia: the course of the ΔVO2/Δ work slope and/or the presence of O2 pulse flattening.7

Recently, Guazzi et al8 published a 2016 focused update on this methodology in apparently healthy individuals and selected patient populations, with specific reference to clarifying the etiology and prognosis of exertional dyspnea, as part of a perioperative surgical risk assessment, to evaluate the severity of valvular heart disease and/or HF, and in using these data to assess exercise tolerance and formulate safe and effective exercise prescriptions. Additional promising (but not proven) applications of CPX variables that were briefly discussed included the oxygen uptake efficiency slope, exercise ventilatory power, circulatory power, and the non-invasive determination of cardiac output, as well as complementary assessments (CPX and Doppler echocardiography). This commentary will further address several of these topics, as well as relevant adjunctive and practical applications.

Prognostic Significance of Dyspnea: A Ventilatory or Circulatory Limitation?

The presence of signs or symptoms at rest and during exercise testing may be used to assess prognosis in patients with known or suspected cardiovascular or pulmonary disease. Dyspnea is of particular interest, since it may be a symptom of underlying coronary disease, signifying an exertional “anginal equivalent,” left ventricular dysfunction, or both, as well as pulmonary disorders such as chronic bronchitis or emphysema. Several studies have now shown that patients with self-reported dyspnea, including those with and without known coronary disease, had increased rates of cardiovascular and all-cause mortality as compared with their asymptomatic counterparts.9,10 Similarly, a long-term follow-up study of 2,014 apparently healthy middle-aged men reported an increased mortality rate among those who demonstrated impaired breathing during exercise testing.11

CPX is useful in dyspneic patients with cardiovascular and/or pulmonary diseases who may demonstrate reductions in both V-AT and breathing reserve, the more dominant of which may signify the primary cause of the patient’s exercise intolerance.12 A V-AT <40% of the predicted VO2peak is indicative of a circulatory limitation, whereas a breathing reserve <30%, calculated as 1 minus the ratio of peak VE to maximal voluntary ventilation, suggests ventilatory impairment, especially when accompanied by oxygen desaturation with exercise. Nevertheless, these findings must be interpreted with caution in light of the peak RER which, if <1.1 (particularly <1.0), may signify poor effort, anxiety, or mild disease.

Risk Stratification Prior to Major Surgery

More than 27 million non-cardiac surgical procedures are performed in the United States each year.13 Cardiac and non-cardiac complications can be a major source of morbidity and mortality in the postoperative period. Although age, body habitus, and co-morbid conditions, including diabetes and coronary artery disease, are likely modulators of these complications, recent studies suggest that preoperative levels of physical activity and/or CRF are predictors of short-term surgical outcomes.14

In addition to serving as a prognostic indicator of cardiovascular and all-cause mortality in both apparently healthy and clinically-referred populations, low preoperative CRF may be especially helpful in identifying “at risk” patients undergoing varied surgical procedures, including abdominal aortic aneurysm repair, hepatic transplantation, lung cancer resection, upper gastrointestinal, intra-abdominal, bariatric,15 and coronary artery bypass surgery.16

Although there is no firmly identified causal mechanism that directly links a higher CRF or physical activity level with reduced post-operative complications, one possible explanation is that physically active or fitter patients are simply better able to cope with the physical and cardiac demands created by the trauma of major surgery. A reduced level of CRF may also be associated with greater numbers and greater severity of unhealthy co-morbid conditions that, individually or collectively, may increase mortality.

Another reasonable explanation is that a low level of CRF identifies a patient subset that is more difficult to operate on, requiring longer operative and intubation times, or those characterized by a high-risk, proinflammatory state that may be related to the development of heightened post-operative complications.15 Interestingly, regular physical activity prior to hospitalization for acute coronary syndrome appears to confer protection during the ensuing month relative to mortality and rehospitalization for recurrent cardiac events.17 The potential impact of low preoperative physical activity and CRF on hospitalization and/or surgical outcomes is shown in the accompanying figure.18

Collectively, these data suggest that physical activity or CRF assessments may be helpful as part of the medical evaluation prior to major surgery. Although it remains unclear whether increases in CRF will translate into lower surgical complication rates, regular exercise and a physically active lifestyle may represent a viable method of improving short-term outcomes associated with elective or emergent surgical procedures.

CPX to Assess Valvular Disease/Heart Failure

Because valvular function is critical to aerobic exercise performance, CPX data, most notably the VE/VCO2slope and VO2peak, as well as the associated hemodynamic and symptomatic responses, may be helpful in evaluating the consequences of right- and left-sided valvular heart disease.8 Using the ventilatory classification system (class I, VE/VCO2slope <30.0 [normal]; class II, VE/VCO2slope 30.0–35.9; class III, VE/VCO2slope 36.0–44.9; class IV, VE/VCO2slope ≥45.0) may provide independent and additive information in detecting elevated pulmonary pressures, with progressively higher values indicating greater severity of valvular heart disease and poorer prognosis,19 including asymptomatic patients with severe aortic stenosis and preserved ejection fraction.5 Moreover, a reduced VO2peak may reflect the degree to which valvular dysfunction compromises cardiac output. Since the maximal arteriovenous oxygen difference appears little affected by heart disease, the VO2peak serves to virtually define the pumping capacity of the heart.20 Exertional hypotension and/or associated symptoms, including dyspnea, leading to exercise test termination, may also provide complementary and confirmatory information substantiating a compromised cardiac output, secondary to valvular dysfunction.21

CPX is commonly recommended to establish prognosis in patients with advanced systolic HF, especially those who are being considered for heart transplantation. In a seminal report involving ambulatory patients with severe left ventricular dysfunction, Mancini et al22 found that a VO2peak >14 mL/kg/min yielded comparable survival to those after transplantation. In contrast, a VO2peak <10 mL/kg/min was associated with a significantly poorer survival. Although these levels of CRF remain important prognostic discriminators in HF patients, others have described disparities in prognostic utility when evaluating men and women with a VO2peak between 10 and 18 mL/kg/min.23 In such patients, it has been suggested that correcting VO2peak for lean body mass, calculating peak O2 pulse, a potential index of stroke volume,24,25 assessing the VE/VCO2slope,26 and accounting for beta-blocker therapy,27 may be used to further refine prognosis patients with HF.

To clarify the effects of mid-life CRF on subsequent HF hospitalization and mortality, researchers linked individual subject data from the Cooper Clinic Longitudinal Study in two long-term follow-up reports.28,29 Adjusted hazard ratios (HR) across high (13.8±1.8 METs), moderate (10.9±0.9 METs), and low (8.7±1.1 METs) levels of CRF were 1.0, 1.63, and 3.97, respectively, showing that baseline CRF is an important determinant of subsequent HF mortality.28 In addition, HF mortality rates were lower in fit than in unfit men within each body mass index category, except for the obese cohort. Overall, each 1 MET improvement in mid-life CRF was associated with a 17% lower risk of HF hospitalization in later life (HR 0.83 [0.74–0.93] per MET).29 Collectively, these studies suggest that increased HF hospitalizations and mortality associated with later life may be attenuated by improving CRF in mid-life, irrespective of antecedent HF risks.

CPX in Apparently Healthy Individuals

Although it remains unclear whether a strategy of routine screening exercise testing in asymptomatic adults reduces the risk of premature mortality or major cardiac morbidity,30 it appears that peak or symptom-limited exercise testing may provide independent and additive information to the risk factor profile in predicting long-term survival.31 Numerous studies also suggest that CRF, whether measured directly or estimated from the achieved work rate, is one of the strongest prognostic markers in persons with and without heart disease.2 In healthy men and women, each 1-MET increase in CRF is associated with a 13% and 15% reduction in all-cause mortality and cardiovascular events, respectively. Participants with an aerobic capacity ≥7.9 METs had the most favorable health outcomes.32 Evaluating the resting electrocardiogram for bundle branch block (right or left),33 calculating the Duke Treadmill Score,34 which incorporates signs and/or symptoms of myocardial ischemia, as well as exercise duration, a key correlate of CRF, identifying chronotropic incompetence,35 quantifying heart rate recovery,36 and assessing exertional hypotension,37 ischemic ST-segment depression, anginal symptoms, and exercise-induced premature ventricular contractions,38 can provide additional refinements that improve the prognostic utility of exercise testing, with or without concomitant ventilatory gas exchange measurements.

CPX Data to Gauge Activity Recommendations and Formulate Exercise Prescriptions

The VO2peak and V-AT may be used to identify appropriate recreational and training activities, based on their estimated aerobic requirements (Table 1),39 or to systematically derive the prescribed heart rate and workload for aerobic exercise training, using somatic ratings of perceived exertion (e.g., “fairly light” to “somewhat hard”)40 and symptoms as adjunctive intensity modulators. For example, a healthy individual achieves a VO2peak of 28.0 mL O2/kg/min and a V-AT of 19.6 mL/kg/min; the V-AT corresponded to a heart rate of 120 bpm and a treadmill speed and grade of 3.0 mph and 5%. A treadmill training program was set at this work rate, preceded and followed by warm-up and cool-down, respectively, at a target heart rate of 114?126 bpm. When CPX data are not available, the energy cost of any activity, expressed as METs, can be reasonably estimated from the resting and exercise heart rates, using the heart rate index equation, as shown, with examples (Table 2).41

Because treadmills are widely used in structured exercise regimens in middle-aged and older adults, whose usual daily walking speeds often approximate 2 to 3 miles per hour (mph), the ‘Rule of 2 and 3 mph’ has been suggested to assist in estimating energy expenditure.42 At a 2-mph walking speed at 0% grade, which approximates 2 METs, each 3.5% increase in treadmill grade adds approximately 1 additional MET to the gross energy cost. For persons who can negotiate a faster walking speed (3 mph) on level ground, which approximates 3 METs, each 2.5% increase in treadmill grade adds an additional MET to the gross energy expenditure (e.g., 3.0 mph, 5% grade ~5 METs).

Conclusions

CPX is a valuable clinical tool in evaluating specific patient populations (e.g., dyspnea, valvular heart disease, HF, cardiovascular/pulmonary disease), providing independent and additive data on functional capacity, prognosis, disease severity, and risk stratification, and in assessing perisurgical and postsurgical risk. It is also helpful in formulating exercise prescriptions in persons with and without heart disease, and in recommending safe and effective aerobic activities. In tandem with the previous AHA scientific statement on CPX,43 the just-published focused update8 masterfully offers the clinician evidence-based CPX algorithms for these indications. If a moderate-to-high level of CRF truly exerts a cardioprotective effect that eliminates or markedly reduces any survival benefit from revascularization and/or selected surgical interventions, it has enormous implications for risk stratification and reducing healthcare costs, an urgent national priority. Assessment of CRF can also provide prognostic information beyond conventional risk factor profiling.31 Accordingly, physicians should expand their medical evaluations to include objective data regarding their patient’s CRF for these conditions and situations, either estimated or directly measured via CPX, expressed relative to age and gender norms.

Table 1. Approximate Metabolic Cost of Various Recreational and Training Activities*

*Represents gross caloric expenditure (i.e., includes the resting metabolic needs); net caloric expenditure is used to describe the caloric cost of exercise per se. Caloric requirements have been calculated for a 70-kg person and must be decreased or increased for lighter or heavier weights, respectively. Adapted from Fox et al.39 Copyright 1972 American Heart Association, Inc.

Table 2. Using Modulations in Heart Rate to Estimate Energy Expenditure (METs) During Daily Activities*

The energy cost of any activity, expressed as METs, can be estimated from the resting and exercise heart rates using the equation:

• METs = (6 x Heart Rate Index) – 5

  where the Heart Rate Index equals the activity heart rate divided by the resting heart rate.

• Example #1 A tennis player’s resting heart rate of 60 beats per minute (bpm) is increased to 120 bpm during a tennis match. His MET level is estimated as follows: 120 bpm/60 bpm = 2.0 Heart Rate Index which is multiplied by 6, yielding 12, from which we subtract 5, yielding an estimated 7 METs.

  (120/60 x 6) – 5 = (2 x 6) – 5 = 7 METs

• Example #2 A walker with a resting heart rate of 70 bpm walks at 105 bpm. His estimated MET level is….

  (105/70 x 6) – 5 = (1.5 x 6) – 5 = 4 METs <.li>

Figure 1

Potential impact of major surgery/hospitalization in patients with a reduced preoperative functional capacity and the associated sequelae. Reprinted with permission from Dronkers JJ.18