Methods

The study protocol was approved by the Wake Forest University Medical Center institutional review board, and written informed consent was obtained from all participants. This report is from the screening visit (test 1) and baseline visit (test 2) of a randomized, double-blinded, placebo-controlled pharmacologic clinical trial whose primary outcome was exercise capacity. Participant eligibility was assessed at an initial screening visit, which included medical history, physical examination, blood laboratory results, echocardiogram to document EF and evidence of diastolic dysfunction, and peak CPET (test 1). Approximately 1 week later, participants returned for a second screening visit. If the initial screening visit blood laboratory results were within inclusion criteria, participants entered into a 2-week placebo run-in period. At the subsequent baseline visit, if compliance to the placebo run-in by pill count was ≥80%, participants completed all baseline study assessments including a second peak CPET (test 2).

Patients had New York Heart Association class II to III of ≥1 month’s duration with pEF at rest, echocardiographic evidence of diastolic dysfunction (early diastolic lateral mitral annular velocity <9 cm/s), and no evidence of significant anemia or coronary artery, valvular, infiltrative, pericardial, pulmonary, or renal disease. In addition, only participants with evidence of severe exercise intolerance (exercise time of ≥2 minutes but ≤12 minutes for women or ≤14 minutes for men) were enrolled. Potential participants were initially screened for inclusion by retrospective review of clinic visits and hospital discharge records at the Wake Forest University Medical Center. Of the resultant 273 preliminarily eligible participants, 66 were scheduled for an initial screening visit and 52 met the study criteria and were enrolled.

The multistep screening, education, and quality control CPET protocol is outlined in Appendix 1 (available online). Briefly, ET was performed on a treadmill using the modified Naughton protocol and conducted by the same trained experienced examiner with a master’s degree in exercise physiology. Before each test, participants were screened for any recent acute illness or injury or change in status and were given detailed, standardized, verbal instructions. During the test, participants were encouraged to walk for as long as possible and, once fatigued, to attempt the subsequent stage, resulting in a peak symptom-limited exhaustive effort. Complete calibration of gas concentrations and flow were performed before each test. Metabolic gas exchange was measured continuously during exercise and averaged over 15-second intervals (Medgraphics Ultima, Medical Graphics Corp., St. Paul, Minnesota). Peak oxygen consumption (V o ₂ ) was defined as the average of the 2 highest V o ₂ values for a given 15-second interval within the last 90 seconds of exercise. Ventilatory anaerobic threshold was calculated using standard methods. Ventilation per carbon dioxide (VE/V co ₂ ) slope was determined by measuring the slope across the entire course of exercise. Oxygen uptake efficiency slope was determined by measuring the slope of V o ₂ (milliliters per minute) and log ₁₀ VE (liters per minute) across the entire course of exercise. All tests were evaluated by the exercise physiologist for validity based on a combination of symptoms (dyspnea on exertion and/or fatigue as primary end points) and physiologic measurements (respiratory exchange ratio, heart rate, minute ventilation, respiratory rate) and confirmed if necessary by a cardiologist. To avoid bias, the tester intentionally did not view the results of test 1 immediately before conducting test 2. In addition, validation of the gas exchange unit was conducted before each testing day by performing a 2-stage incremental exercise test in a known, constant test subject. To be validated, V o ₂ and V co ₂ needed to be within 2 SDs of the usual known value at each workload.

Means are expressed using ± SD or 10th and 90th percentiles. Within-subject variability from test 1 to test 2 was quantified by within-subject absolute change (i.e., increase or decrease from test 1 to test 2). Paired t test was used to test for a statistical difference between the test 1 and test 2 values. Bland–Altman plot was used to visually assess whether the magnitude of within-subject variability in peak V o ₂ varied with magnitude of the measurements. Reliability of CPET outcome measurements from the screening visit to the baseline visit was tested by Pearson correlations and intraclass correlations. One-sided 95% confidence intervals of Pearson correlations were made using Fisher’s z transformation. For each variable, the coefficient of variation was defined as (within-subject SD/within-subject mean) × 100%. Significance was set at a p value <0.05.

Results

Participants were predominantly white women with a history of hypertension and New York Heart Association functional class II symptoms ( Table 1 ). Tests 1 and 2 were separated by an average of 23 ± 13 days. Compliance by pill count to the placebo run-in period was excellent (96%). No adverse events occurred during or after any peak CPET. In 3 participants, the screening visit CPET was not considered a valid peak test and was repeated 2 weeks later. Reasons were (1) abnormal gait and coordination resulting in early fatigue and test termination in 2 participants and (2) test ended primarily owing to knee pain in 1 participant. The 2 participants with abnormal gait and coordination were coached on proper mechanics immediately after the screening visit CPET, with good results. The participant with initial knee pain returned after a bout of nonsteroidal anti-inflammatory drugs and completed the repeated CPET with no pain. In each case, the repeated screening visit CPET was considered valid and was used in this analysis.

Peak V o ₂ and ventilatory anaerobic threshold were nearly identical on the 2 tests. Within-subject peak V o ₂ demonstrated high agreement between tests as shown by Bland–Altman analysis ( Figure 1 ). Reliability of CPET parameters was excellent ( Table 2 ) and was similar across age and gender ( Tables 3 and 4 ). Exercise time increased significantly from test 1 to test 2. Likewise, VE/V co ₂ slope was significantly greater in test 2 than in test 1 ( Table 5 ).

Bland–Altman plot for change in peak oxygen consumption versus mean peak oxygen consumption for tests 1 and 2.

Table 4

Effects of gender on cardiopulmonary exercise reliability

	Women (n = 42)				Men (n = 10)
	Test 1	Test 2	R	ICC	Test 1	Test 2	R	ICC
Exercise time (sec)	568 ± 107	590 ± 116	0.92	0.902	611 ± 126	632 ± 151	0.89	0.877
Oxygen uptake (ml/kg/min)	13.8 ± 1.9	13.9 ± 1.8	0.79	0.795	16.8 ± 2.7	16.3 ± 3.2	0.88	0.865
Oxygen uptake (ml/min)	1,183 ± 234	1,187 ± 221	0.89	0.888	1,614 ± 306	1,571 ± 348	0.89	0.885
Heart rate (beats/min)	133 ± 24	132 ± 21	0.93	0.927	110 ± 24	107 ± 26	0.94	0.934
Systolic blood pressure (mm Hg)	171 ± 18	168 ± 20	0.8	0.789	165 ± 18	161 ± 16	0.61	0.616
Diastolic blood pressure (mm Hg)	74 ± 9	72 ± 8	0.71	0.694	74 ± 12	72 ± 9	0.86	0.84
Carbon dioxide production (ml/min)	1,321 ± 251	1,338 ± 256	0.84	0.842	1,870 ± 348	1,824 ± 406	0.84	0.84
Respiratory exchange ratio	1.12 ± 0.06	1.13 ± 0.07	0.55	0.55	1.16 ± 0.06	1.17 ± 0.07	0.84	0.852
Ventilation per carbon dioxide slope	30.7 ± 4.5	31.5 ± 4.6	0.86	0.852	29.4 ± 4.9	29.7 ± 4.4	0.91	0.908
Oxygen uptake at ventilatory threshold (ml/min)	790 ± 170	783 ± 157	0.71	0.716	1,070 ± 231	1,074 ± 252	0.68	0.705
Oxygen uptake efficiency slope	1,455 ± 333	1,460 ± 378	0.81	0.811	2,040 ± 577	1,944 ± 532	0.89	0.886

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