Methods

We evaluated 16 men with stable CHD, defined angiographically (≥70% diameter narrowing of ≥1 major coronary artery; 15 patients) and/or scintigraphically (reversible myocardial perfusion defects; 7 patients). These patients had been selected to participate in a study designed to evaluate the safety of an ischemic exercise training program. Before beginning the training program, patients underwent the present study. They had to have had ≥2 Bruce protocol treadmill tests positive for myocardial ischemia (≥1 mm STD), with the latest one within the year preceding the study. Electrocardiographic signs of ischemia had to have occurred before the last stage of the exercise test. To ensure that maximal exercise performance would be achieved and not be limited by ischemic discomfort, the patients who consistently experienced exertional angina pectoris were excluded. Patients were also excluded if they had significant electrocardiographic abnormalities at rest that could render electrocardiographic interpretation problematic, such as voltage criteria for left ventricular hypertrophy and ST-segment depression >0.5 mm, if they had significant arrhythmias, or if they were taking digitalis. Patients were instructed not to consume caffeine-containing beverages or food after the preceding midnight and to refrain from eating and smoking 4 hours before each test. They were also required to avoid unusual or intense exercise the day before and on the day of exercise testing to exclude a confounding warm-up effect. The hospital ethics committee approved the study, and all patients gave written informed consent.

The 3 symptom-limited maximal exercise tests were randomly performed at a similar time of day under similar physiologic conditions and without interrupting patients’ usual medications for both ethical and practical reasons. At least 1 week separated each exercise test, and the 3 exercise tests were completed within 4 to 6 weeks. The treadmill protocols were performed using a motorized treadmill (Quinton, Bothell, Washington), and the ergocycle test was performed using an electromagnetically braked ergocycle (Quinton) in upright position. The exercise protocols consisted of a stepwise treadmill protocol (Bruce protocol) and 2 ramp protocols, one on the treadmill and the other on the ergocycle. The stepwise Bruce treadmill protocol consisted of 3-minute increments of treadmill speed and incline, and the treadmill ramp protocol was developed to use a linear increase in walking speed that was coupled with a curvilinear increase in treadmill grade to yield a constant increase in the work rate. The patients were not allowed to support their weight on the handrails during the treadmill exercise tests. Both the treadmill and ergocycle ramp protocols were individualized, with continuous gradual work rate (Watts) increments to impose a continuous increase of 10% of the peak V̇O ₂ /min, as recommended by the guidelines for exercise testing. Strong verbal encouragement to exercise to the greatest tolerated symptoms of fatigue and/or dyspnea was given by the personnel supervising the exercise tests. Both patients and supervising personnel were kept unaware of the maximal values obtained on the other exercise tests. The exercise was terminated if the patients were unable to maintain the workload (speed and grade on the treadmill or ≥40 rpm on the ergocycle) or in the presence of a decrease in SBP >10 mm Hg, dizziness, or significant arrhythmia.

Respiratory gas analysis was performed using a metabolic cart (Quinton QMC, Bothell, Washington), as previously described. In brief, oxygen consumption (V̇O ₂ ), carbon dioxide production (V̇CO ₂ ), and ventilation per minute were continuously recorded. The respiratory exchange ratio was derived by the quotient V̇CO ₂ /V̇O ₂ and the slope of the oxygen consumption versus work rate (ΔV̇O ₂ /Δwork rate) was calculated according to the current guidelines of exercise testing. The peak values were calculated at the maximal achieved exercise and determined by the highest that had ≥2 other 5-breath averages within 2 mlO ₂ × kg ⁻¹ × min ⁻¹ . Maximal exercise was defined by the fulfillment of these conditions: (1) an inability to sustain the workload; (2) Borg-rated perceived exertion scale (scale of 0 to 10) ≥8 of 10; and (3) respiratory exchange ratio >1.10.

The at rest values were recorded and averaged for 3 minutes while the patients quietly awaited the start of the test in the exercise position. During exercise, the electrocardiogram was continuously monitored, and a 12-lead tracing was obtained every 30 seconds and as needed. The occurrence of sustained 1-mm STD (compared to the upright at rest baseline value), measured 80 ms after the J-point in 3 consecutive averaged QRS complexes (checked against the raw data) in any of the 12 leads was identified. The RPP at this latter point was determined and defined as the ischemic threshold. The STD at peak effort was also measured. At the conclusion of the 3 tests, the peak STD adjusted to the greatest RPP common to the 3 tests was determined for each test. The amplitude of the R wave of precordial lead V ₅ was measured at rest, at 1-mm STD, and at peak exercise. Blood pressure was measured using an automated device (Model 412, Quinton) and validated using an earphone by the cardiologist supervising all tests. The blood pressure was determined every 2 minutes, or more frequently, to document as closely as possible the values at 1-mm STD and at peak exercise. The mean arterial pressure was calculated using the following equation: mean arterial pressure = SBP + [0.33 + (heart rate × 0.0012)] × (SBP − diastolic blood pressure). In contrast to the original formula [mean arterial pressure = diastolic blood pressure × 1/3 (SBP − diastolic blood pressure)], the former formula takes into account the disproportionate reduction of diastole compared to systolic time when heart rate increases during exercise.

Data are expressed as the mean ± SD. Comparisons of respiratory gas data and hemodynamic and ischemic parameters among the tests were performed using a general linear model of repeated measurement design using Greenhouse-Geiser post hoc comparisons. Differences among the 3 exercise protocols and the use of medication were compared using univariate analysis of variance. Student’s paired t test was performed to compare individual data between 2 specific exercise protocols. A generalized linear model for individual observations was also derived to analyze the longitudinal variable tendency. p Values <0.05 were considered statistically significant. Data were analyzed using the statistical package Statistical Analysis Systems, version 9.1.3 (SAS Institute, Cary, North Carolina).

Results

The 16 study subjects, aged 56 to 72 years, completed all exercise tests. The history and clinical characteristics of the subjects are summarized in Table 1 . Although >1/2 of the patients had had a previous myocardial infarction, all had a left ventricular ejection fraction of ≥50%. All patients but 1 had a previous coronary angiogram showing ≥70% coronary artery narrowing (7 of these patients had also undergone myocardial nuclear imaging showing reversible perfusion defects). The remaining patient, who had not undergone coronary angiography, had had a previous myocardial infarction and subsequently underwent a nuclear imaging study showing a reversible perfusion defect. Nearly all patients had previously undergone a coronary revascularization procedure. No patient had any change in their clinical condition or cardiovascular medications during the study period. All tests were well tolerated.

Table 1

Clinical characteristics and hemodynamic and gas exchange data measured in at rest exercise position and at peak exercise (all men, n = 16)

Pt. No./Age (years)	Clinical Features							At Rest (HR [beats/min], SBP/DBP [mm Hg])			At Peak Exercise (Ex. Time [min], RER, HR [beats/min], SBP/DBP [mm Hg])
	AP	MI	HBP	DM	Drugs	PCI	CABG	Bicycle Ramp	Bruce Treadmill	Ramp Treadmill	Bicycle Ramp	Bruce Treadmill	Ramp Treadmill
1/56	0	+	0	0	BB	0	0	65, 149/92	65, 159/90	64, 159/94	9.0, 1.23, 132, 252/92	10.0 ⁎ , 1.14, 133, 206/88	15.0 ⁎ , 1.03, 132, 191/74
2/59	0	+	0	0	—	+	0	64, 120/80	68, 137/74	69, 147/85	14.0 ⁎ , 1.31, 184, 215/112	15.6 ⁎ , 1.29, 181, 182/90	17.7 ⁎ , 1.34, 178, 190/80
3/60	0	+	0	+	ACE, CCB, D	+	0	74, 153/71	76, 163/79	64, 154/63	12.0 ⁎ , 1.08, 155, 215/93	12.0 ⁎ , 1.06, 154, 220/80	13.9 ⁎ , 0.97, 142, 195/72
4/61	0	+	0	0	BB	0	+	52, 135/73	51, 154/85	57, 116/70	15.9 ⁎ , 1.20, 122, 170/83	11.9 ⁎ , 1.18, 122, 174/81	15.3 ⁎ , 1.16, 113, 162/61
5/64	0	+	+	0	BB	0	+	47, 146/74	50, 152/83	47, 129/69	9.7 ⁎ , 1.28, 118, 190/85	9.7, 1.14, 120, 156/75	12.7 ⁎ , 1.08, 106, 162/NA
6/67	0	+	0	0	ACE, D	0	0	71, 125/80	78, 133/70	68, 131/55	10.7 ⁎ , 1.33, 145, 231/106	6.4 ⁎ , 1.13, 123, 195/77	13.8 ⁎ , 1.12, 131, 194/84
7/56	+	0	0	0	BB, N	+	+	65, 132/79	59, 124/80	63, 132/75	12.7 ⁎ , 1.17, 151, 210/81	9.0 ⁎ , 1.36, 152, 192/80	13.6 ⁎ , 1.30, 142, 215/63
8/67	+	0	0	+	BB	+	0	50, 130/55	64, 132/68	61, 125/54	10.8 ⁎ , 1.14, 110, 205/81	12.0 ⁎ , 1.09, 120, 190/89	14.7 ⁎ , 1.03, 108, 172/65
9/61	0	0	0	0	ACE, CCB	+	0	62, 120/63	55, 133/64	67, 131/61	12.5, 1.15, 144, 191/66	12.9 ⁎ , 1.23, 157, 160/80	13.0 ⁎ , 1.15, 152, 168/70
10/62	0	0	+	0	BB, ACE	0	+	65, 169/86	69, 182/86	68, 148/73	15.6 ⁎ , 1.07, 157, 250/102	6.4 ⁎ , 1.10, 152, 259/97	11.6 ⁎ , 1.24, 155, 240/80
11/65	0	0	0	0	BB	+	0	54, 151/65	51, 136/75	65, 141/81	10.7 ⁎ , 1.21, 149, 205/83	9.6 ⁎ , 1.17, 143, 209/90	14.3 ⁎ , 1.21, 155, 200/95
12/71	0	0	+	0	BB	0	+	64, 168/90	67, 153/75	61, 179/84	8.5 ⁎ , 1.10, 136, 225/101	5.6 ⁎ , 1.22, 135, 184/87	11.3 ⁎ , 1.04, 116, 184/76
13/59	+	+	0	0	BB, N	0	0	59, 125/71	58, 138/85	67, 114/85	12.7 ⁎ , 1.15, 120, 193/54	10.9 ⁎ , 1.14, 124, 172/NA	14.7 ⁎ , 1.13, 119, 157/53
14/69	+	+	0	+	BB, ACE, CCB, N	0	+	72, 131/79	85, 124/72	71, 148/83	8.5 ⁎ , 1.11, 114, 166/72	5.5, 1.00, 130, 144/67	12.9 ⁎ , 1.13, 113, 154/73
15/71	+	+	+	0	BB, CCB	0	0	62, 124/82	48, 107/63	53, 111/62	13.5, 1.13, 145, 205/79	9.4 ⁎ , 1.10, 125, 171/65	14.3 ⁎ , 1.14, 134, 229/NA
16/72	+	+	0	0	ACE	+	0	89, 147/84	82, 134/75	85, 152/81	11.0 ⁎ , 1.12, 152, 219/97	6.9 ⁎ , 1.07, 149, 191/69	13.5 ⁎ , 1.10, 149, 214/84

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