Role of cardiopulmonary stress testing in heart failure management

Heart failure (HF) is a global problem of epidemic proportions. In the United States HF affects more than 5 million people currently, with 500,000 newly diagnosed cases every year. It is a syndrome of multiple etiologies and can involve systolic and/ or diastolic dysfunction. The risk of death due to HF has increased partly because advances in technology have decreased the age-adjusted death rates for cardiac diseases, especially those of ischemic origin, and, therefore, increased the prevalence of HF through longer survival.


Introduction
Heart failure (HF) is a global problem of epidemic proportions.In the United States HF affects more than 5 million people currently, with 500,000 newly diagnosed cases every year.It is a syndrome of multiple etiologies and can involve systolic and/ or diastolic dysfunction.The risk of death due to HF has increased partly because advances in technology have decreased the age-adjusted death rates for cardiac diseases, especially those of ischemic origin, and, therefore, increased the prevalence of HF through longer survival.
Direct measurement of ventilation and gas exchange during exercise is called a cardiopulmonary stress test (CPX).Cardiopulmonary stress testing measures multiple parameters that vary with alterations in cardiac and pulmonary function.The most important variables are expiratory ventilation (V ̇E), pulmonary gas exchange expressed as oxygen uptake (V ̇O2 ), carbon dioxide output (V ̇CO 2 ), cardiac rate and rhythm, and blood pressure.A composite set of variables measured by CPX links cardiovascular and pulmonary responses to the metabolic demands of exercise.Exercise intolerance is a characteristic feature of HF with symptoms, such as shortness of breath, fatigue, or both, which are usually out of proportion to the level of exertion.Therefore, the assessment of exercise intolerance can be used to predict the degree of cardiac impairment, stratify risk, and optimize therapy.

Assessment of disease severity, risk stratification, and prognostication
In HFrEF the most important use of CPX is to triage patients at the appropriate time to advanced HF therapies, such as implantation of ventricular assist devices (VADs) and cardiac transplantation.In HFpEF it is used to determine disease severity by unmasking symptoms with exercise.In both cases it is also used to guide management toward optimal medical regimens or to triage to advanced surgical therapies for HF.
The New York Heart Association (NYHA) functional class is a subjective classification addressing a patient's functional capacity. 6To overcome the subjectivity of this classification exercise testing, such as CPX, has been used to make objective decisions about the treatment of chronic HF. 7 Peak oxygen consumption (V ̇O2 ) has been shown to correlate with functional capacity and mortality.This relationship between oxygen consumption and outcomes was first reported by Mancini et al. 1 More recently, other measurements obtained during metabolic exercise tests have been shown to predict mortality in patients with end stage HF.][10] Russell et al showed that the NYHA functional class predicts exercise parameters and can be used for assessing disease severity and outcomes. 11The study by Russell also demonstrated that there is a significant difference in the peak V ̇O2 , V ̇E/ V ̇CO 2 slope, and exercise time in patients with NYHA functional class II symptoms compared to those with NYHA functional class III/IV symptoms.

11
In the era of evidence-based medicine, risk stratification using multivariable scores has reliable, robust scores using CPX as one of the parameters.

15-22
The Heart Failure Survival Score by Aaronson et al has proved to be better than using peak oxygen consumption alone. 18The score by Myers et al 16,17 also used V ̇O2 , V ̇E/ V ̇CO 2 slope, end-tidal CO 2 pressure, OUES, and heart rate recovery.The V ̇E/ V ̇CO 2 slope was the strongest predictor of cardiovascular risk for mortality.Poor ventilatory control in heart failure can manifest as a crescendo-decrescendo pattern without interposed apnea called exercise oscillatory ventilation (EOV).Peak circulatory power is the product of peak V ̇O2 and peak systolic blood pressure.Therefore addition of these extra parameters such as Exercise Oscillatory Ventilation (EOV), the lowest V ̇E/ V ̇CO 2 ratio, peak circulatory power, V ̇E/ V ̇CO 2 slope, and OUES, produced an optimal score for predicting the risk for mortality in this population.23,24   Exercise ventilatory power (EVP) is the ratio between peak systolic blood pressure and the V ̇E/ V ̇CO 2 slope.Forman et al 25 showed that using ≤ 3.5 mmHg for the EVP as a cutoff for high risk had better prognostic discrimination capability and predict survival.Subsequently, Borghi-Silva et al 26 used Doppler echocardiographic recordings throughout the CPX tests in patients with HFrEF and showed that lower EVPs indicated severely impaired peak V ̇O2 and cardiac output response to exercise with consequent impairment of right heart function and hemodynamics affecting the pulmonary system.This result showed that a lower EVP indicated increased disease severity.
The relative increase in V ̇O2 to maximal work rate (WR) (change in V ̇O2 /change in WR) has been proposed as an indicator of cardiac efficiency and aerobic generation of adenosine triphosphate.In normal subjects this increases linearly and represents a surrogate index of cardiac output.In ventricular dysfunction during exercise, this parameter may plateau and fail to reach a value ≥ 10 mL/min/W.Additionally, a flat Δ V ̇O2 /ΔWR was associated with increased systolic pulmonary artery pressure and decreased RV systolic function.

27,28
The Exertional Oscillatory Ventilation (EOV) has been found to be an important prognostic index in HF.The pathophysiological mechanisms of EOV are still not fully understood.Several factors, including decreased cardiac output, suboptimal chemoreceptor responses, reduced ventilator control, RV dysfunction, abnormal pulmonary hemodynamics, and delayed information transfer related to arterial CO 2 levels from the pulmonary capillaries to peripheral and central chemoreceptors secondary to impaired ventricular function, probably affect the EOV.Hence, the addition of EOV to CPX parameters would be useful for better risk stratification and prognostication.The utilization of the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score for prognostication helps identify cardiovascular mortality and the requirement of heart transplantation.The MECKI score consists of six laboratory values, such as hemoglobin, sodium, creatinine clearance calculated by the Modification of Diet in Renal Disease (MDRD) equation, the left ventricle ejection fraction (LVEF), the percentage of V ̇O2 max, and the V ̇E/ V ̇CO 2 slope.

29-38
Respiratory muscle performance (RMP) has emerged to be an important factor in risk stratifying patients with chronic HF.The strong association of RMP to indices of pulmonary vascular hemodynamics is valuable in the context of a plateau in change in V ̇O2 /change in WR.However, measurement of RMP has limitations.Despite these challenges RMP still appears to have a role in patients with HF for diagnosis, prognosis, and therapy.

Determination of myocardial contractile reserve
The strongest correlation with V ̇O2 max was with the peak left ventricular systolic tissue velocity (S') during exercise.Resting echocardiographic parameters, like the ejection fraction of the left ventricle, correlated poorly with exercise capacity.In idiopathic dilated cardiomyopathy, V ̇O2 max reflected myocardial contractile reserve in ambulatory patients.However, the slope of V ̇E/ V ̇CO 2 was not useful in this population.In another study with non-ischemic cardiomyopathy patients, BNP and left ventricular inotropic reserve correlated well with CPX.

Use of CPX for guiding therapy
The use of CPX in HFrEF and HFpEF is well documented in the current literature.Some representative studies are listed in Table 1.The use of CPX has been demonstrated in both patients with HFrEF and those with HFpEF to help with risk stratification and prognostication.Figure 2 shows a suggested algorithm for using CPX to risk stratify and guide management of HF.
The Ventilatory Threshold (VT), also called the anaerobic threshold, assesses exercise intensity, ventilation, and metabolism and has potential use in therapeutic interventions.In HF, aerobic exercise training should be performed below the VT.Intermittently, exercise above VT can be done but with caution. 51,52Hence assessment of VT can be used to determine exercise prescriptions in HF.In a small study CPX guided exercise rehabilitation was safe and effective for patients with HF.

Summary
Cardiopulmonary exercise testing has evolved considerably since the first report of its use in HF in 1991.5][56] Multiple small studies have demonstrated the utility of CPX in diagnosis, risk stratifica-tion for mortality, and prognostication of HFrEF and HFpEF The use of CPX in grading diastolic dysfunction has been reported in a small study of individuals with HFpEF. 57Future research investigations may be needed to conclusively include the newer parameters discussed (EOV, OUES, EVP and circulatory power) before these can be used routinely in CPX assessments. 58CPX is, therefore, a highly useful, comprehensive test to evaluate, risk stratify, and guide therapy in the present day management of HF.

Bandera et al 28 2014 Prospective
Cardiopulmonary stress test, HFpEF, HFrEF, V ̇O2 max, V ̇E/ V ̇CO 2 Author Affiliation: Nandini Nair is a transplant cardiologist in the Department of Internal Medicine/Division of Cardiology at Texas Tech University Health Sciences Center in Lubbock, TX.Enrique Gongora is a cardiothoracic /transplant surgeon at Memorial Cardiac and Vascular Institute in Hollywood, FL.HFrEF, HFpEF 136 A flat ΔVO 2 /ΔWR reflects impaired functional phenotype