Prognostic value of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. The Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) project.

BACKGROUND: Although cardiopulmonary exercise (CPX) testing in patients with heart failure and reduced ejection fraction is well established, there are limited data on the value of CPX variables in patients with HF and preserved ejection fraction (HFpEF). We sought to determine the prognostic value of select CPX measures in patients with HFpEF. METHODS: This was a retrospective analysis of patients with HFpEF (ejection fraction ≥ 50%) who performed a CPX test between 1997 and 2010. Selected CPX variables included peak oxygen uptake (VO2), percent predicted maximum oxygen uptake (ppMVO2), minute ventilation to carbon dioxide production slope (VE/VCO2 slope) and exercise oscillatory ventilation (EOV). Separate Cox regression analyses were performed to assess the relationship between each CPX variable and a composite outcome of all-cause mortality or cardiac transplant. RESULTS: We identified 173 HFpEF patients (45% women, 58% non-white, age 54 ± 14 years) with complete CPX data. During a median follow-up of 5.2 years, there were 42 deaths and 5 cardiac transplants. The 1-, 3-, and 5-year cumulative event-free survival was 96%, 90%, and 82%, respectively. Based on the Wald statistic from the Cox regression analyses adjusted for age, sex, and ß-blockade therapy, ppMVO2 was the strongest predictor of the end point (Wald χ(2) = 15.0, hazard ratio per 10%, P < .001), followed by peak VO2 (Wald χ(2) = 11.8, P = .001). VE/VCO2 slope (Wald χ(2)= 0.4, P = .54) and EOV (Wald χ(2) = 0.15, P = .70) had no significant association to the composite outcome. CONCLUSION: These data support the prognostic utility of peak VO2 and ppMVO2 in patients with HFpEF. Additional studies are needed to define optimal cut points to identify low- and high-risk patients.

Comprehensive analysis of cardiopulmonary exercise testing and mortality in patients with systolic heart failure: the Henry Ford Hospital cardiopulmonary exercise testing (FIT-CPX) project.

BACKGROUND: Many studies have shown a strong association between numerous variables from a cardiopulmonary exercise (CPX) test and prognosis in patients with heart failure with reduced ejection fraction (HFrEF). However, few studies have compared the prognostic value of a majority of these variables simultaneously, so controversy remains regarding optimal interpretation. METHODS AND RESULTS: This was a retrospective analysis of patients with HFrEF (n = 1,201; age = 55 ± 13 y; 33% female) and a CPX test from 1997 to 2010. Thirty variables from a CPX test were considered in separate adjusted Cox regression analyses to describe the strength of the relation of each to a composite end point of all-cause mortality, left ventricular assist device implantation, or heart transplantation. During a median follow-up of 3.8 years, there were 577 (48.0%) events. The majority of variables were highly significant (P < .001). Among these, percentage of predicted maximum V˙O2 (ppMV˙O2; Wald = 203; P < .001; C-index = 0.73) was similar to VE-VCO2 slope (Wald = 201; P < .001; C = 0.72) and peak V˙O2 (Wald = 161; P < .001; C = 0.72). In addition, there was no significant interaction observed for peak respiratory exchange ratio <1 vs ≥1. CONCLUSIONS: Consistent with prior studies, many CPX test variables were strongly associated with prognosis in patients with HFrEF. The choice of which variable to use is up to the clinician. Renewed attention should be given to ppMV˙O2, which appears to be highly predictive of survival in these patients.

The ventilatory anaerobic threshold in heart failure: a multicenter evaluation of reliability.

BACKGROUND: The ventilatory threshold (VT) is usually determined by visual assessment of the point where the rate of elimination of carbon dioxide (VCO(2)) increases nonlinearly with respect to oxygen uptake (VO(2)) (the V-Slope method). We quantified the reliability of VT determination using data from a multicenter study in patients with heart failure. METHODS AND RESULTS: The Fix-Heart Failure-5 study of cardiac contractility modulation enrolled 428 patients from 50 centers in the United States. Cardiopulmonary exercise tests were performed at baseline and 12, 24, and 50 weeks after randomization, which provided 1679 tests. The VT was determined from each test in a core laboratory by 2 independent readers. VT could not be determined for 276 tests (16.4% indeterminate). Inter-observer variability (quantified by the 95% limits of agreement, LoA, expressed as a percent of the mean value) was 20.2% between the 2 readers, with a coefficient of variation (CV) of 7.3%. Intra-observer variability was assessed by resubmitting (blinded) 179 tests to the same readers; the LoA was 24.7% for reader 1 and 16.9% for reader 2, with CVs of 6.1 and 8.9%, respectively. Ninety-one tests were submitted to 2 additional readers at a second core lab. Inter-observer variability in the second lab was 26.7% with a CV of 9.6%. Inter-laboratory variability was 21.4%, with a CV of 7.7%. CONCLUSIONS: Inter-observer, intra-observer, and inter-site variation in determining the VT should be considered when using the VT as an end point in clinical trials of heart failure.

Peak aerobic capacity predicts prognosis in patients with coronary heart disease.

BACKGROUND: It is unknown if contemporary preventive treatments such as statins or primary percutaneous coronary intervention in patients with coronary heart disease (CHD) have rendered obsolete the use of measured exercise capacity for assessment of future risk and prognosis. Using a sample of patients from 2 clinical sites, most of whom were taking beta-blockade, antiplatelet, and statin therapy, we hypothesized that peak oxygen consumption (Vo(2)) would remain a strong and independent predictor of all-cause and cardiovascular-specific mortality in men and women with CHD. METHODS: We studied 2,812 patients with CHD between 1996 and 2004. All-cause and cardiovascular disease-specific mortality served as end points. RESULTS: In all men and women and in a subgroup of patients following evidence-based care, peak Vo(2) remained a strong predictor of all-cause death, with every 1 mL x kg(-1) x min(-1) increase in peak Vo(2) associated with an approximate 15% decrease in risk of death. Among men, a peak Vo(2) (mL x kg(-1) x min(-1)) below approximately 15 was associated with the highest risk, whereas a peak Vo(2) above approximately 19 was associated with a low rate and risk for annual all-cause mortality. Among women, a peak Vo(2) below approximately 12 was associated with the highest risk, whereas a peak Vo(2) above approximately 16.5 was associated with the lowest rate and risk for annual all-cause mortality. CONCLUSIONS: In men and women with CHD, peak Vo(2) remains an independent predictor of all-cause and cardiovascular-specific mortality.

Quality assurance and cardiopulmonary exercise testing in clinical trials.

BACKGROUND: Peak oxygen uptake (VO2) measured during cardiopulmonary exercise testing (CPX) is often used as an outcome measure in clinical trials. The purposes of this study are (a) to report the outcomes of a quality assurance (QA) procedure instituted in multisite clinical trials by a CPX data core laboratory and (b) to report a normative VO2 reference dataset for future use. METHODS: The CPX laboratory at each site participating in a multisite clinical trial in which Henry Ford Hospital served as the CPX data core laboratory was required to pass a standardized QA procedure before site activation and regularly thereafter. Data were compared with a VO2 reference dataset (pilot data) and assessed for test-retest reproducibility. VO2 data that represented a normal physiologic response were used to develop a final normative VO2 reference dataset. RESULTS: Between 2003 and 2006, 81 laboratories submitted 144 baseline QA tests. Of these, 34% did not initially meet the passing criteria, largely because of poor test-retest reproducibility. Among all QA tests submitted to the core laboratory, 159 unique volunteers had exercise data that met the criteria to be entered into the final normative VO2 reference dataset. Within this dataset, the mean coefficient of variation for VO2 between the test and retest was 5.1%. CONCLUSION: A standardized QA procedure can be used to identify aberrant data and minimize the variability of VO2 measured in a clinical trial or the routine evaluation of patients.

Greater improvement in cardiorespiratory fitness using higher-intensity interval training in the standard cardiac rehabilitation setting.

PURPOSE: We tested the hypothesis that higher-intensity interval training (HIIT) could be deployed into a standard cardiac rehabilitation (CR) setting and would result in a greater increase in cardiorespiratory fitness (ie, peak oxygen uptake, (·)VO2) versus moderate-intensity continuous training (MCT). METHODS: Thirty-nine patients participating in a standard phase 2 CR program were randomized to HIIT or MCT; 15 patients and 13 patients in the HIIT and MCT groups, respectively, completed CR and baseline and followup cardiopulmonary exercise testing. RESULTS: No patients in either study group experienced an event that required hospitalization during or within 3 hours after exercise. The changes in resting heart rate and blood pressure at followup testing were similar for both HIIT and MCT. (·)VO2 at ventilatory-derived anaerobic threshold increased more (P < .05) with HIIT (3.0 ± 2.8 mL·kg⁻¹·min⁻¹) versus MCT (0.7 ± 2.2 mL·kg⁻¹·min⁻¹). During followup testing, submaximal heart rate at the end of stage 2 of the exercise test was significantly lower within both the HIIT and MCT groups, with no difference noted between groups. Peak (·)VO2 improved more after CR in patients in HIIT versus MCT (3.6 ± 3.1 mL·kg⁻¹·min⁻¹ vs 1.7 ± 1.7 mL·kg⁻¹·min⁻¹; P < .05). CONCLUSIONS: Among patients with stable coronary heart disease on evidence-based therapy, HIIT was successfully integrated into a standard CR setting and, when compared to MCT, resulted in greater improvement in peak exercise capacity and submaximal endurance.