Cardiopulmonary Exercise Testing and Outcomes in Women With Heart Failure—Examining the “Female Advantage”

Abstract

Cardiopulmonary exercise testing (CPET) has long been shown to provide important prognostic information in patients with heart failure. Since the 1991 publication by Mancini et al, 1 CPET, and specifically peak oxygen consumption (pVO2), has been used in prognostication for patients with heart failure being assessed for cardiac transplantation. pVO2 is essentially an assessment of cardiac reserve (the ability of the heart to increase cardiac output), and patients unable to achieve a pVO2 of � 14 mL/kg/min were shown to have improved survival with transplantation as opposed to without transplantation. However, multiple subsequent studies have shown that women with heart failure have better overall survival than do their male counterparts, despite women having a comparatively low pVO2, 2-5 placing into question the role of CPET in prognostication for women with heart failure. pVO2is, of course, far from the only parameter assessed with CPET, despite being arguably the most used by heart failure clinicians. Also commonly used is ventilatory response; the response of minute ventilation to CO2 production (VE/VCO2 slope), which is an indicator of the presence of heart failureerelated physiological consequences such as V:Q mismatch and aberrancies of autonomic function. VE/VCO2 has been shown to be of prognostic valueinheartfailure,withhighervaluescorrespondingtoworse prognosis, and specifically may be more predictive of adverse heart failure outcomes in women. 4-6 There are many potential reasons for the sex-related discrepancy in the predictive value of CPET parameters. Women were not well represented in the initial studies done to derive the equations for prediction of maximum VO2, resulting in a sex bias on this basis alone. There is also a significant male predominance in studies assessing CPET for prognosis. The reasons for this are likely related to the demographics of women with heart failure: they tend to be older at the onset of heart failure, have more heart failure with preserved ejection fraction, and have more comorbidities. Women are also less likely to be able to exercise to the levels believed to be necessary for CPET analysis. Exercise effort in CPET is assessed by the peak respiratory exchange ratio (pRER)dthe ratio of expired CO2 to O2 consumeddwhich is an indicator of cardiometabolic stress. A pRER of > 1.0 is considered indicative of adequate exercise effort and has been believed to be necessary for prognostic reliabilityofpVO2,withmoststudiesexcludingpatientswhofail to achieve this level. The combination of demographics of women with heart failure and the reduced likelihood of these women exercising to achieve a pRER of > 1.0 would exclude many women from most CPET trials. Thus, the women who end up being enrolled in CPET trials are by definition only the “bestexercising”womenwithheartfailure.Thisissupportedby the fact that the women in CPET trials are younger, have lower bodymassindex(BMI),andhavelessatrial fibrillation,whichis much different from the demographics of the women we see in other heart failure trials. Differences in female vs male physiology may also contribute to the apparent difference in predictive value of CPET in women compared with men, and perhaps the traditionally accepted absolute values for predictive cutoffs are not as applicable to women as they are for men. 7 Perhaps we are using the wrong CPET parameters for women. In a recently published article, a comprehensive evaluation of multiple CPET parameters with regard to mortality in patients with heart failure was undertaken. 5 Looking specifically at their results in women, that study also showed that among women, pVO2 was not associated with survival at 1 year. The authors suggest that percentage of predicted maximum VO2, which quantifies the patient’s absolute pVO2 according to age and sex, may be the preferred prognostic indicator. The study did not exclude patients with a pRER 1.0. This finding may be particularly relevant to women, who traditionally may have been excluded from CPET studies based on an inability to achieve “adequate” exercise levels.