Clinical Trial
Development of a Cardiopulmonary Exercise Prognostic Score for Optimizing Risk Stratification in Heart Failure: The (P)e(R)i(O)dic (B)reathing During (E)xercise (PROBE) Study

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Abstract

Background

Cardiopulmonary exercise testing (CPET) provides powerful information on risk of death in heart failure (HF). We sought to define the relative and additive contribution of the 3 landmark (CPET) prognostic markers—peak oxygen consumption (VO2), minute ventilation/carbon dioxide production (VE/VCO2) slope, and exercise periodic breathing (EPB)—to the overall risk of cardiac death and to develop a prognostic score for optimizing risk stratification in HF patients.

Methods and Results

A total of 695 stable HF patients (average LVEF: 25 ± 8%) underwent a symptom-limited CPET maximum test after familiarization and were prospectively tracked for cardiac mortality. At multivariable Cox analysis EPB emerged as the strongest prognosticator. Using a statistical bootstrap technique (5000 data resamplings), point estimates, and 95% confidence intervals were obtained. Thirty-two configurations were adopted to classify patients into a given cell, according to EPB presence or absence and values of the 2 other covariates. Configurations without EPB and with VE/VCO2 slope ≤30 were not significantly different from 0 (reference value). Statistical power of configurations increased with higher VE/VCO2 slope and lower peak VO2. This prompted us to formulate a score including EPB as a discriminating variable, the (P)e(R)i(O)dic (B)reathing during (E)xercise (PROBE), which ranges between -1 and 1, with zero as reference configuration, that would help to optimize the prognostic accuracy of CPET-derived variables. The greatest PROBE score impact was provided by EPB, followed by VE/VCO2 slope, whereas peak VO2 added minimal prognostic power.

Conclusions

EPB with an elevated VE/VCO2 slope leads to the highest and most precise PROBE score, whereas no additional risk information emerges when EPB is present with a peak VO2 ≤10 mL O2·kg−1·min−1. PROBE score appears to provide a step forward for optimizing CPET use in HF prognostic definition.

Section snippets

Methods

This was a multicenter study consisting of HF patients from the cardiopulmonary exercise laboratories at San Paolo Hospital, Palo Alto Health Care System, Palo Alto, CA; Virginia Commonwealth University, Richmond, VA; and the LeBauer Cardiovascular Research Foundation, Greensboro, NC. Six hundred and ninety-five subjects diagnosed to have HF, who underwent a symptom-limited CPET between June 1998 and June 2007, were included. Subjects with significant obstructive lung disease evidenced by a

Results

The case series comprised 695 patients; 31% from Italy (Cardiopulmonary Laboratory at S. Paolo Hospital, Milano) and 61% from the United States (23% from Virginia Commonwealth University; 26% from Palo Alto Health System Care and 20% from the LeBauer Research Foundation). Table 1 shows the baseline clinical characteristics of patient population. Distribution of the covariates is shown in Table 2. The median follow-up time was 24 months and there were 134 cardiac-related deaths during this

Discussion

EPB is an abnormal pathophysiological phenomenon that occurs at a rate that varies from 18% to 30% across different HF populations and carries key information on the clinical evolution of HF syndrome.6, 7, 8, 9, 19, 20, 21 The pathogenesis of EPB, although complicated, seems to derive from a combination of deregulatory pathways involved in the mechanical and neural feedback control of the cardiopulmonary system.19, 20 EPB prevalence is similar in both systolic and diastolic HF.22 Present

Conclusions and Perspectives

The present results underscore the importance of systematic recognition, analysis, and reporting of EPB occurrence in the CPET summary report. EPB alone is a strong prognostic marker, but when combined with other established CPET variables, the prognostic power of CPET is enhanced. The value of EPB is supported by the following: 1) PROBE scores excluding EPB were not significant predictors of risk with the exception of patients with a high VE/VCO2 slope; 2) in patients already at high risk

Disclosures

None.

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    Supported by a Grant from the Monzino Foundation, Milano-ITALY,

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