Ms. S is a 65-year-old woman with chronic obstructive pulmonary disease, coronary artery disease, and chronic heart failure with preserved ejection fraction. She is admitted for dyspnea. Three months prior to admission, she developed progressive dyspnea on exertion, which has progressed to the point that she is unable to do more than walk around her home before needing to stop to rest. Her vital signs and physical exam are unremarkable. Her medications include aspirin, a beta-blocker, an angiotensin-converting enzyme inhibitor, and a statin with adequate adherence. She rarely uses her albuterol inhaler and has not smoked for more than 10 years.
Chest radiography shows slightly hyper-inflated lungs with no infiltrates. Echocardiogram shows a left ventricular ejection fraction of 50%, type 1 diastolic dysfunction, and normal valves. Pulmonary function tests are consistent with GOLD stage I obstructive lung disease. None of these findings explain Ms. S's worsening dyspnea on exertion. Both the clinician and the patient are puzzled by the lack of answers this work-up has provided. In the meantime, Ms. S continues to suffer from dyspnea and the resultant poor quality of life.
Dyspnea is one of the most common symptoms seen in the health care setting (1). Most of its causes can be determined through history, physical exam, and some basic tests (2). In some cases, such as Ms. S's, the cause of the patient's poor tolerance can be difficult to pinpoint. In still other cases, once the cause is explained, questions of prognosis and treatment plans come into play. Cardiopulmonary stress testing (CPX) can be used both for diagnostic and prognostic purposes. Done during exercise, the test measures respiratory gas exchange on a breath-by-breath basis to evaluate clinically relevant metabolic parameters that may reveal the cause of poor exercise capacity and help formulate treatment plans (3). Although most patients with dyspnea are found to have a cardiovascular or pulmonary issue, processes that present with this symptom are diverse. Thus, the patient population that could benefit from testing is also diverse; hormonal, myopathic, metabolic, and psychogenic conditions can all be differentiated via CPX (2).
CPX has been evolving for over half a century to lend prognosis and give objective data for patient monitoring (2). However, recent data suggest that this comprehensive test is underutilized—usually due to the need for personnel who are proficient in the administration and interpretation of the test, limited training by specialists in the technique, and lack of understanding of the value of CPX by practicing clinicians (2). There is new interest in using CPX because of its ability to provide prognostic as well as diagnostic information for patients with pulmonary disease and heart disease, in addition to those with unexplained dyspnea.
CPX offers greater diagnostic information regarding cardiac structure and function. Ventilatory gas exchange measurements provide a wide array of unique and clinically useful information (2). When clinicians send a patient for CPX, data can reveal abnormalities of oxygen delivery/utilization, abnormalities of gas exchange efficiency, and abnormalities in breathing mechanics. These data can be used to pinpoint whether the cardiac and respiratory systems are working in tandem or if there are issues in either system.
CPX is different from cardiac stress testing or pulmonary function testing in that it links the cardiovascular and pulmonary systems together. A major function of the cardiovascular system is gas exchange, supplying oxygen and other fuels to working muscles as well as removing carbon dioxide and other metabolites. The heart, lungs, and pulmonary and systemic circulations form a single circuit for exchange of respiratory gases between the environment and the cells of the body. Under steady state, respiratory oxygen uptake (VO2) and carbon dioxide output (VCO2) measured at the mouth are equivalent to oxygen utilization (QO2) and carbon dioxide production (QCO2) occurring in the cell; thus, external respiration equals internal respiration. CPX directly measures VO2, VCO2, and airflow (minute ventilation, tidal volume, and respiratory rate) on a breath-by-breath basis, using a non-rebreather valve connected to a metabolic cart (3). Anaerobic threshold, defined as the highest oxygen uptake attained without a sustained increase in blood lactate concentration, is also obtained. Breathing reserve or the capacity for ventilation is calculated as one minus the ratio of peak exercise minute ventilation (Ve) to maximal voluntary ventilation.
Normal peak VO2 (≥85% predicted) can be seen in patients with dyspnea caused by anxiety, obesity, or very mild cardiopulmonary disease. Low peak VO2 (<85% predicted) has a variety of causes. Combining low peak VO2 with low AT can help delineate cause. Research with heart failure patients undergoing CPX indicate that AT is reproducible and is an effort-independent parameter (4). Low peak VO2 with normal AT can be seen in patients with deconditioning or coronary disease if breathing reserve is normal or in patients with ventilatory impairment if breathing reserve is low. A circulatory impairment is usually the root of the patient's dyspnea when low peak VO2 and low AT are revealed along with normal breathing reserve. Low peak VO2, low AT, and decreased breathing reserve are seen if dyspnea is due to a combination of circulatory and ventilatory impairment.
The normal cardiac response to exercise includes increased systolic arterial pressure in association with reduced vascular resistance. This facilitates increased muscle perfusion. Cardiac output is increased by accelerated heart rate and increased stroke volume. In patients with cardiovascular disease, pathological limitations to these increases in cardiac output restrict maximal exercise. Peak VO2 is a robust marker of cardiovascular performance because both central pathology (systolic and diastolic dysfunction and chronotropic incompetence, or the failure to achieve 85% of age-predicted maximum heart rate) and peripheral pathology (heart failure-related vasoconstriction and skeletal muscle myopathy) can all lead to a decrease in peak VO2 (5, 6).
Respiratory response to exercise occurs because of increased intramuscular carbon dioxide production. Homeostatic capacity to increase ventilation efficiently results in a steady partial pressure of carbon dioxide. In pulmonary disease, ventilatory limitation leads to hypercapnea and possibly hypoxemia. However, it is also known that patients with pulmonary disease may have intrinsic skeletal muscle abnormalities that diminish their exercise capacity (2, 5, 6).
CPX is a useful tool to differentiate between cardiac and pulmonary causes. CPX is also useful in the evaluation of dyspneic patients with combined cardiac and pulmonary diseases who may have a reduction in both capacities as well as in musculoskeletal function (3, 6). In addition, CPX responses have been demonstrated as valuable in prognostic consideration for transplants and risk stratification paradigms (6). Information gleaned from CPX has also been used for optimizing rate-adaptive pacemakers, assessing the need for surgical repair of congenital heart disease, and assessing the functional significance of regurgitant valvular heart disease.
One of the most studied areas where CPX has been useful is advanced systolic heart failure. Findings of low maximum VO2 (VO2 max) as well as chronotropic incompetence have both been shown to have poor prognosis in this patient population (3). Of note, peak VO2 is often used clinically in lieu of VO2max due to the impracticality of showing a plateau in VO2 against an increasing work rate in the clinical population. Therefore, the terms are used interchangeably in this article (7).
In the Veterans Administration Heart Failure Trial (V-HeFT), the mortality rate of patients failing to achieve less than a VO2 max of 14.5 mL/kg was double that of patients able to achieve that value. Peak VO2 has also been used to predict survival of patients referred for cardiac transplant, with 14 mL/kg being the threshold below which survival seemed to decrease. In addition, CPX helps to better characterize the pathophysiological basis of dyspnea, which can have clinical and prognostic implications (2). Use of CPX to gauge the level of preserved ejection fraction in heart dysfunction is also now supported by several studies (6).
Insight into the pathophysiology and severity of pulmonary disease is also a useful characteristic of CPX. In chronic obstructive pulmonary disease, VO2 is predictive of overall survival and can be used as a standard for developing a pulmonary rehabilitation program. Effects of pulmonary hypertension that may not have been visible at rest can be elucidated during a CPX. In addition, the test can be used for preoperative evaluation of patients with pulmonary disease since exercise limitation is one of the best determinants of how emphysema and severe airflow limitation will respond to lung volume reduction surgery (5). Poor exercise capacity is also seen in patients with pulmonary diseases who are most likely to benefit from lung transplant.
Evaluation of unexplained dyspnea, similar to that of the patient case discussed earlier, is therefore best elucidated with CPX. The mechanism for exercise intolerance can be evaluated with the goal of reproducing the symptoms to detect coinciding cardiopulmonary abnormalities.
Back to the case
So, what about Ms. S, our patient with progressive dyspnea? She was found to have shortness of breath after 8 minutes of a ramping protocol and had to stop the test. She had no ischemic changes on electrocardiography during the test or during the recovery period. Her peak VO2 was low (<85% of predicted) and her AT was normal (>40% of predicted). Her breathing reserve was normal as well (>30%). Thus, even though Ms. S has heart failure with preserved ejection fraction and mild chronic obstructive pulmonary disease, these conditions did not seem to drive her current report of dyspnea. With the help of CPX, it was found that deconditioning and obesity were the causes of her limitation. A management plan that included exercise and weight loss was developed based on the patient's CPX results to help her regain quality of life.
CPX is an underused test. CPX can evaluate both pulmonary and cardiovascular systems as well as the interaction between the two and can be used to gain valuable diagnostic and prognostic information, particularly in patients with heart disease, respiratory illnesses, and even musculoskeletal or neurological abnormalities that may affect breathing. For patients like Ms. S, CPX can be used to evaluate unexplained exertional dyspnea. Having concrete data to support a diagnosis in this area can be useful both for diagnosis and to formulate a plan of treatment.