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Ischemic threshold varies in response to different types of exercise in patients with chronic stable angina
lschemic threshold varies in response different types of exercise in patients chronic stable angina
to with
The effects of different types of exercise on ischemic threshold were studied in 33 patients with chronic stable angina, documented coronary artery disease, and reproducible positive exercise test results. On average, ST segment depression developed at a significantly higher heart rate and rate-pressure product when the standard modified Bruce protocol was preceded by a warm-up period (113 + 13 vs 119 k 15 beats/min and 18,813 f 3882 vs 20,357 2 4227 beats/min X mm Hg, respectively; p < 0.05 and
Giuseppe Pupita, MD, Juan Carlos Kaski, MD, Alfred0 R. Galassi, MD, Margarita Vejar J, MD, Filippo Crea, MD, and Attilio Maseri, FRCP. London, England
Little information is available regarding the possible effects of different types of exercise on effort tolerance in patients with chronic stable angina. It is conceivable that exercise tolerance may vary in response to different types of effort as observed in some patients exhibiting the so-called “warm-up phenomenon” or “angina of first effort.“l Furthermore, ambulatory ECG monitoring2 and exercise testing3 in patients with chronic stable angina have shown that within individuals exercise-induced ischemia may develop at variable workloads. Whether variable exercise tolerance can result from different types of effort and whether this occurs
Prom the Cardiovascular mersmith Hospital.
Unit,
Received
Feb.
for publication
Royal 15, 1989;
Postgraduate accepted
Medical April
Reprint requests: Giuseppe Pupita, MD, Cardiovascular smith Hospital, DuCane Road, London W 12, United 4/l/13690
School,
Ham-
3, 1989. Unit, Kingdom
Hammer-
only in certain types of coronary artery disease patients is not known. To elucidate this, the response to different types of exercise was studied in 33 patients with chronic stable angina, positive exercise test results, and documented coronary artery disease. METHODS Patients.
We studied 33 patients (26men and 7 women), aged45 to 75 years (mean 60 + 8 years), with chronic stable angina pectoris without appreciable changesin symptoms during the preceding 3 months, positive exercisetest results (horizontal or downsloping ST segment depression L 1 mm), and angiographically documentedcoronary artery disease(internal diameter reduction 250% of at least one major branch). Sixteen patients had had a previousmyocardial infarction. Duration of angina rangedfrom 0.5 to 8 years (mean 3.7 k 2.3). Clinical characteristics of the patients are listed in Table I. All patients werein sinusrhythm, and nonehad evidence of heart failure, cardiomyopathy, or valvular disease.No patient had ECG alterations that could interfere with the 539
540
Pupita et al.
Table
I. Clinical,
American
ECG, and angiographic Age
Patient
Sex
lvri
F M F M M F M M M M M M M F M M M F M M M M M M M M F
66 51
61 45 45 69 63 68 61 45 63 61 65 61 62
4
6 8 9 10 11 12 13
14 15 16
51
17
58 52 62 72 61 64 63 63 52 63 69 15 64 51 66 60 64
18 19
20 21 22 23 24 25 26 27 28 29 30 31 32 33 Ant,
anterior;
E, exertional;
M
F M M M M Inf, inferior;
MI. myocardial
data
._
Preuious MI
Type of angina
Ant. Inf N Inf Ant N Inf N N Ant, Inf Inf N Ant, Inf Ant Inf N N Ant N N N N N N Inf Inf N Inf Inf N N N Ant infarction;
E+R Asymptomatic Asymptomatic E E E+R E E+R Asymptomatic E E E E E+R Asymptomatic E E+R E E Asymptomatic E E+R E E
Asymptomatic E E+R E E E+R E E Asymptomatic N, normal;
interpretation of ST segment changes, and no patient was taking digitalis. Nitrates and calcium entry-blocking agents were withdrawn at least 2 days before study and P-blocking agents 4 days before study. Each patient had undergone at least two treadmill exercise tests with the modified Bruce protocol and was familiar with the test environment before entering the study. Written informed consent was obtained from all patients. Study protocol. To evaluate the influence of different types of exercise on ischemic threshold, two subsets of patients were studied: in 16 patients with low exercise tolerance (<6 minutes on the modified Bruce protocol), results on the modified Bruce protocol were compared to those obtained with another protocol, which consisted of the modified Bruce protocol preceded by a warm-up period of 10 minutes at 1.0 mph and 0% inclination. In another 17 patients with intermediate or high exercise tolerance (29 minutes on the modified Bruce protocol), results on the modified Bruce protocol were compared to those obtained with an exercise protocol that was started abruptly at the stage immediately preceding the one in which 1 mm ST segment depression occurred during the modified Bruce protocol.
--.__Varinble angina threshold
September 1989 Heart ~ownal
No. of diseased LYSW~.Y
No
I
Yes No No No Yes
L!
No Yes No NO Yes
1
‘> :i 2
2
Yes Yes No No NO Yes No NO No Yes No Yes Yes No NO
2 1
R, rest.
Exercise tests were performed on consecutive days and their sequence was randomized; before each test at least I hour of complete rest was allowed. One week later all patients underwent a control exercise test while they were not receiving treatment (with the modified Bruce protocol), which was repeated 2 hours later immediately after the administration of 0.5 mg of sublingual nitroglycerin. Exercise testing. Results of 12-lead ECG and blood pressure monitoring (cuff sphygmomanometer) were recorded during the control period and at l-minute intervals during exercise and for 6 minutes during recovery. The level of the ST segment 80 msec after the J point was calculated after signal averaging by a computer-assisted system (CASE, Marquette 12, Marquette Electronics Inc., Milwaukee, Wise.) in all 12 leads. The calculated values were printed out, along with the heart rate, against time in trend format. The ECG lead showing the greatest ST segment depression was selected for analysis. For each test, heart rate and heart rate-systolic blood pressure product at 1 mm ST segment depression were measured. Cardiac catheterization. Selective coronary arteriography was performed in all patients within 6 months of the exercise study by means of the Judkins technique. In 12
Volume
118
Number
3
Exercise type and ischemic threshold
p
Group
p=Ns
I
I
1
I
MB
W
MB
A
1. Effects of warm-up and abrupt exercise on ratepressure product at 1 mm ST segment depression in responders(0) and nonresponders(0). A, abrupt exercise; MB, modified Bruce protocol; W, warm-up exercise. Fig.
patients, after diagnostic angiography, an appropriate view of the most severestenosiswasselectedand mantained for subsequentarteriography. After a control arteriography each patient performed 2 minutes of sustained isometric handgrip exercise at two thirds of a predetermined maximum grip strength with a commercially available device (Stoelting, Inc., Chicago, Il.). Coronary arteriography was repeated immediately after cessationof handgrip exercise. After 10 minutes intracoronary isosorbidedinitrate (2 mg) wasadministered and coronary arteriography repeated. In 11other patients the effect of intracoronary isosorbideonly was assessed. Control coronary arteriograms and those obtained after handgrip exercise and isosorbidedinitrate were analyzed by two independent observers. Coronary artery luminal diameters at the site of the stenosisand of the closestangiographically normal segmentwere measuredby an automated edge contour detection computer analysis system (Computerized Angiographic Analysis System, Pie Medical, Neptune, N.J.). The size of the stem of the Judkins catheter wasusedfor calibration to absolutemeasurement units in millimeters, and correction was made for radiographic pincushion distortion. Data analysis. Statistical analysis was performed by Student’s t test for paired and unpaired data asappropriate. A value of p < 0.05 wasconsideredstatistically significant. RESULTS Effect of different
types of exercise. The heart rate at 1 mm ST segment depression increased from 113 + 13 beats/min (mean k SD) during the stan-
dard modified Bruce exercise test to 119 + 15 beats/ min 0, < 0.05) when the modified Bruce protocol was preceded by a lo-minute warm-up period. The ratepressure product at 1 mm ST segment depression also increased from 18,813 Jo 3682 beats/min x mm
I
MB
in CAD
I
Group II
p c 0.001
p <0.05
I
NTG
I
MB
54 I
I
NTG
2. Effects of sublingual administration of 0.5 mg nitroglycerin on rate-pressureproduct at 1 mm ST segment depressionin groupsI and II. MB, modified Bruce protocol with no treatment; NTG, modified Bruce protocol with 0.5 mg sublingual nitroglycerin. Fig.
Hg to 20,357 k 4227 beats/min X mm Hg 03 < 0.01) (Fig. 1). Analysis of results in individual patients showed that after warm-up in 8 of the 16 patients rate-pressure product at 1 mm ST segment depression increased by at least 2000 beats/min X mm Hg. In these patients heart rate and rate-pressure product at 1 mm ST segment depression increased from 115 + 13 beats/min to 130 f 8 beats/min and from 18,978 + 3318 beats/min X mm Hg to 22,135 f 3301 beats/min X mm Hg, respectively. In the remaining eight patients warm-up resulted in little or no change in heart rate or rate-pressure product at 1 mm ST segment depression (from 111 + 14 beats/min to 109 f 14 beats/min and from
18,648 -t 4241 beats/min X mm Hg to 18,579 +- 4491 beats/min X mm Hg, respectively. The abrupt start exercise on average did not result in significant changes in heart rate (from 129 + 19 beats/min to 128 f 16 beats/min; p = NS) or rate-pressure product (from 21,112 +- 3839 beats/min x mm Hg to 20,410 f 3242 beats/min X mm Hg; p = NS) at 1 mm ST segment depression (Fig. 1). However, in 3 of the 17 patients who underwent abrupt exercise testing a decrease ~2000 beats/min X mm Hg of rate-pressure product at 1 mm ST segment depression was noted. Heart rate at 1 mm ST segment depression decreased from 147 + 4 beats/min during the standard modified Bruce protocol to 134 +- 10 beats/min, and rate-pressure product at 1 mm ST segment depression decreased from 25,453 f 2374 beats/min X mm Hg to 21,436 + 4209 beats/min X mm Hg. In the remaining 14 patients the heart rate changed from 125 t 18 beats/min to
542
Pupita et al.
American
Normal segment
Stenotic
Group I
Group II
p < 0.01
p<0.05
Group I
September 1989 Heart Journal
segment Group II p=NS
p
1
B
HG
B
HG
B
HG
B
HG
Fig. 3. Changesin coronary luminal diameter of normal and stenotic segmentsin responseto isometric
handgrip exercise in groups I and II. 3, basal; HG, handgrip.
126 -+ 17 beats/min and the rate-pressure product from 20,182 f 3463 beats/min X mm Hg to 20,190 + 3149 beats/min X mm Hg. Therefore of the 33 patients included in the study, 11 showed changes in ischemic threshold 22000 beats x mm Hg in response to different types of exercise (variable threshold, group I), whereas the other 22 had little change in threshold (fixed threshold, group II). Reproducibility of results during exercise testing. For each individual patient the results obtained during the two exercise tests performed while patients were not receiving treatment with the modified Bruce protocol were compared. Differences between tests results in heart rate and rate-pressure product achieved at 1 mm ST segment depression were 6.1 f 4.2 beats/min (range 0 to 12) and 994 * 599 beats/min X mm Hg (range 0 to 1850), respectively. In none of the patients was a difference ~2000 beats/min X mm Hg in rate-pressure product at 1 mm ST segment depression observed. In group I the difference in heart rate and rate-pressure product at 1 mm STsegment depression between tests (7.5 + 3.2 beats/min and 1270 + 510 beats/min X mm Hg, respectively) was higher than in group II (5.0 + 2.6 beats/min and 855 + 603 beats/min X mm Hg, respectively); this difference, however, did not achieve statistical significance. Effect of acute administration of nitrates. In group I exercise testing after the administration of sublingual nitroglycerin resulted in a marked increase in heart rate (123 f 18 beats/min vs 145 + 19 beats/ min; p < 0.001) and rate-pressure product (20,744 + 4240beats/min X mmHgvs 25,641 + 4547 beats/min X mm Hg; p < 0.001) at 1 mm ST segment depression. In group II sublingual nitroglycerin increased heart rate and rate-pressure product at 1 mm ST segment depression from 120 * 18 beats/min to
128 +- 16 beats/min (p < 0.001) and from 19,624 * 3740 beats/min X mm Hg to 20,689 ~fi 3406 beats/min x mm Hg 0, < 0.05) (Fig. 2). The increase in heart rate and rate-pressure product at 1 mm ST segment depression after sublingual nitroglycerin was significantly greater in group I than in group II (22 ? 8 beats/min vs 8 + 9 beats/min; 4896 + 1998 beatslmin X mm Hg vs 1064 + 2145 beats/min x mm Hg, respectively; all p < 0.01). Furthermore, in all patients in group I sublingual nitroglycerin increased the rate-pressure product at 1 mm ST segment depression by at least 2000 beats/min x mm Hg, whereas this occurred in only four patients in group II. Angiographic data. The effect of isometric handgrip exercise was assessed in five patients in group I and seven patients in group II; the effect of intracoronary isosorbide dinitrate was evaluated in seven patients in group I and 16 patients in group II. In both groups handgrip exercise resulted in a significant and comparable increase in heart rate (from 72 + 16 beats/min to 95 +- 21 beats/min in group I and from 68 * 12 beats/min to 91 + 18 beatslmin in group II; both p < 0.01) and systolic blood pressure (from 140 + 27 to 172 f 32 mm Hg in group I and from 136 + 19 to 168 -+ 23 mm Hg in group II; both p < 0.01). In none of the patients did angina or ST segment changes develop during handgrip exercise. After handgrip exercise the diameter of the normal segment decreased significantly and to a comparable extent in both groups (from 2.89 -t 1.37 mm to 2.72 + 1.36 mm in group I and from 2.36 ? 0.41 mm to 2.27 * 0.35 mm in group II; p < 0.01 and CO.05, respectively). Similarly, intracoronary isosorbide dinitrate caused a significant increase in the diameter ofthenormalsegmentin bothgroups (from2.9 + 1.13 mmto3.16 f 1.05mmingroupIandfrom2.83 & 0.62
Volume Number
118 3
Exercise type and ischemic threshold in CAD Stenotic segment
Normal segment
6
543
Group I
Group II
pco.05
p-co.05
Group I
Group II p =0.053
2.5
1 /I
0.5 -
1’
I 0
ISDN
I
I
B
ISDN
O-
I B
I
I
1
ISDN
B
ISDN
Fig. 4. Changesin coronary luminal diameter of normal and stenotic segmentsin responseto 2 mg intra-
coronary isosorbidedinitrate in groups I and II. B, basal;ISDN, isosorbidedinitrate. mm to 3.04 it 0.59 mm in group II; both p < 0.05)
(Fig. 3 and 4). After handgrip exercise the diameter of the stenotic segment decreased significantly in group I (from 1.22 + 0.39 mm to 0.99 -t 0.35 mm; p < 0.01) but not in group II (from 1.12 + 0.22 mm to 1.16 f 0.30 mm; p = NS). In group I there was a significant increase in the diameter of the stenosis after intracoronary isosorbide dinitrate (from 1.16 + 0.33 mm to 1.52 2 0.39; p < O.OOl), whereas in group II changes were smaller (from 1.25 + 0.33 mm to 1.36 -t 0.39 mm, p = 0.053) (Figs. 3 and 4). DISCUSSION
The results of this study show that ischemic threshold, assessed by rate-pressure product at 1 mm of ST segment depression, varies depending on the type of exercise performed in a sizable proportion of patients. Whereas the inclusion of a warm-up period tends to increase the ischemic threshold, an abrupt start of the effort can decrease it. These changes were observed in about one third of the patients included in the study, and the magnitude of changes in ischemic threshold observed with different types of exercise was significantly greater than the spontaneous variations observed in the same patients during control exercise tests. To date only a few studies have approached the problem of the relationship between type of exercise and variability of ischemic threshold. Twenty years ago MacAlpin and Kattusl reported that warm-up resulting from a previous exercise improved exercise tolerance in some patients with coronary artery disease. More recently, Jaffe and Quinn4 observed less ECG evidence of ischemia in 21 of 22 patients during
the second of two bicycle exercise tests when the second test had been preceded by a 30-minute warm-up period. Along these lines Garber et a1.5 observed that by performing a submaximal steady-state exercise test at 70% of the peak heart rate achieved with a standard Bruce protocol, patients had a lower ischemic threshold than during the control exercise. Opposite results were obtained by Redwood et al.,6 who did not show significant changes in angina threshold in response to different exercise protocols; however, that report did not provide objective measurements of ischemic threshold and data regarding individual patients were not shown. Although in the present study we do not provide direct evidence of the mechanism responsible for changes in ischemic threshold observed with different types of exercise, our findings indicate that the presence of dynamic stenosis could have played an important role. This view is supported by the fact that during different types of exercise significantly different rate-pressure products (a reliable index of myocardial oxygen consumption7) were achieved at similar levels of ischemia. This is also consistent with the findings of Jaffe and Quinn,4 who observed less ECG evidence of ischemia despite similar workloads when the exercise had been preceded by a warm-up period. A decreased contractility resulting from consecutive testing, as suggested by Williams et al.,8 is a very unlikely explanation in our patients, because exercise tests were performed on different days and in random order. Furthermore, a decreased contractility would not explain the reduction in ischemic threshold observed when the exercise was started abruptly. Although, as hypothesized by Rutenberg,g it cannot be ruled out that changes in preload or in
544
Pupita et al.
peripheral vascular resistance might be responsible for the “warm-up phenomenon,” various lines of evidence indicate that changes in ischemic threshold in these patients were due to dynamic changes in core.nary vasomotor tone at the site of the stenosis. Indeed all patients in whom changes related to the type of exercise were observed had a marked improvement in exercise capacity with sublingual nitrates, a phenomenon that has been shown to be related to a reduced coronary tone at the site of the stenosis.10-13 Furthermore, the administration of intracoronary nitrates in these patients resulted in a significant dilatation of the luminal diameter of the stenosis, whereas isometric handgrip exercise caused significant coronary constriction as also observed by otherP14; it is remarkable that this was observed only in patients in group I and not in patients in group II. Thus ischemic threshold can vary in patients with chronic stable angina in response to different types of exercise. This occurs mainly in patients with the potential for dynamic stenosis; in these patients it appears reasonable to postulate that different types of effort might have a different capacity for affecting coronary tone at the site of critical stenosis. REFERENCES
1. MacAlpin RN, Kattus AA. Adaptation to exercise in angina pectoris. The electrocardiogram.during treadmill walking and coronary angiographic findings. Circulation 1966;33:183-201. 2. Deanfield JE, Maseri A, Selwyn AP, Ribeiro P, Chierchia S, Kirkler S, Morgan M. Myocardial ischemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;2:753-8.
American
September 1989 Heart Journal
3. Crea F, Margonato A, Kaski JC, Rodriguez Plaza 1,. Meran DO, Davies G, Chierchia S, Maseri A. Variability of result,s during repeat exercise stress testing in patients with stable angina pectoris: role of dynamic coronary flow reserve. Ai~l HEART
J 1986;112:249-54.
4. Jaffe MD, Quinn NK. Warm-up phenomenon in angina pectoris. Lancet 1.980;2:934-6. 5. Garber CE, Warren LS, Hanna G, Carleton RA, Heller GV. Does exercise intensity influence the ischemic threshold? .JAm Co11 Cardiol 1988;11:24A. 6. Redwood DR, Rosing DR, Goldstein RE, Beiser GD, Epstein SE. Importance of the design of an exercise protocol in the evaluation of patients with angina pectoris. Circulation 1971: 43:618-28. 7. Sheffield LY. Exercise stress testing. In: Braunwald E, ed. Heart disease. Philadelphia: WB Saunders, 1984258-78. 8. Williams DO, Bass TA, Gewirtz H, Most AS. Adaptation to the stress of tachycardia in patients with coronary artery disease: insight into the mechanism of the warm-up phenomenon. Circulation 1985;71:687-92. 9. Rutenberg HL. Of pre-loads, afterload and warm-ups [Letter 1. Lancet 1981;1:272. 10. Kaski JC, Rodriguez Plaza L, Meran DO, Araujo L, Chierchia S, Maseri A. Improved coronary supply: prevailing mechanism of action of nitrates in chronic stable angina. AM HEART J 1985;110:238-45. 11. Brown BG, Bolson E, Peterson RB, Pierce CD, Dodge HT. The mechanism of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. Circulation 1981; 64:1089-97. 12. Brown BG, Lee AB, Bolson E, Dodge HT. Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation 1984;70:18-24. 13. Gage JE, Hess OM, Murakami T, Ritter M, Grimm J, Krayenbuehl HP. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986;73:865-76. 14. Matsuda Y, Ogawa H, Moritani K, Fujii T, Yoshino F, Katayama K, Miura T, Toma Y, Matsuda M, Kusukawa R. Coronary angiography during exercise-induced angina with ECG changes. AM HEART J 1984;108:959-66.
to with
The effects of different types of exercise on ischemic threshold were studied in 33 patients with chronic stable angina, documented coronary artery disease, and reproducible positive exercise test results. On average, ST segment depression developed at a significantly higher heart rate and rate-pressure product when the standard modified Bruce protocol was preceded by a warm-up period (113 + 13 vs 119 k 15 beats/min and 18,813 f 3882 vs 20,357 2 4227 beats/min X mm Hg, respectively; p < 0.05 and
Giuseppe Pupita, MD, Juan Carlos Kaski, MD, Alfred0 R. Galassi, MD, Margarita Vejar J, MD, Filippo Crea, MD, and Attilio Maseri, FRCP. London, England
Little information is available regarding the possible effects of different types of exercise on effort tolerance in patients with chronic stable angina. It is conceivable that exercise tolerance may vary in response to different types of effort as observed in some patients exhibiting the so-called “warm-up phenomenon” or “angina of first effort.“l Furthermore, ambulatory ECG monitoring2 and exercise testing3 in patients with chronic stable angina have shown that within individuals exercise-induced ischemia may develop at variable workloads. Whether variable exercise tolerance can result from different types of effort and whether this occurs
Prom the Cardiovascular mersmith Hospital.
Unit,
Received
Feb.
for publication
Royal 15, 1989;
Postgraduate accepted
Medical April
Reprint requests: Giuseppe Pupita, MD, Cardiovascular smith Hospital, DuCane Road, London W 12, United 4/l/13690
School,
Ham-
3, 1989. Unit, Kingdom
Hammer-
only in certain types of coronary artery disease patients is not known. To elucidate this, the response to different types of exercise was studied in 33 patients with chronic stable angina, positive exercise test results, and documented coronary artery disease. METHODS Patients.
We studied 33 patients (26men and 7 women), aged45 to 75 years (mean 60 + 8 years), with chronic stable angina pectoris without appreciable changesin symptoms during the preceding 3 months, positive exercisetest results (horizontal or downsloping ST segment depression L 1 mm), and angiographically documentedcoronary artery disease(internal diameter reduction 250% of at least one major branch). Sixteen patients had had a previousmyocardial infarction. Duration of angina rangedfrom 0.5 to 8 years (mean 3.7 k 2.3). Clinical characteristics of the patients are listed in Table I. All patients werein sinusrhythm, and nonehad evidence of heart failure, cardiomyopathy, or valvular disease.No patient had ECG alterations that could interfere with the 539
540
Pupita et al.
Table
I. Clinical,
American
ECG, and angiographic Age
Patient
Sex
lvri
F M F M M F M M M M M M M F M M M F M M M M M M M M F
66 51
61 45 45 69 63 68 61 45 63 61 65 61 62
4
6 8 9 10 11 12 13
14 15 16
51
17
58 52 62 72 61 64 63 63 52 63 69 15 64 51 66 60 64
18 19
20 21 22 23 24 25 26 27 28 29 30 31 32 33 Ant,
anterior;
E, exertional;
M
F M M M M Inf, inferior;
MI. myocardial
data
._
Preuious MI
Type of angina
Ant. Inf N Inf Ant N Inf N N Ant, Inf Inf N Ant, Inf Ant Inf N N Ant N N N N N N Inf Inf N Inf Inf N N N Ant infarction;
E+R Asymptomatic Asymptomatic E E E+R E E+R Asymptomatic E E E E E+R Asymptomatic E E+R E E Asymptomatic E E+R E E
Asymptomatic E E+R E E E+R E E Asymptomatic N, normal;
interpretation of ST segment changes, and no patient was taking digitalis. Nitrates and calcium entry-blocking agents were withdrawn at least 2 days before study and P-blocking agents 4 days before study. Each patient had undergone at least two treadmill exercise tests with the modified Bruce protocol and was familiar with the test environment before entering the study. Written informed consent was obtained from all patients. Study protocol. To evaluate the influence of different types of exercise on ischemic threshold, two subsets of patients were studied: in 16 patients with low exercise tolerance (<6 minutes on the modified Bruce protocol), results on the modified Bruce protocol were compared to those obtained with another protocol, which consisted of the modified Bruce protocol preceded by a warm-up period of 10 minutes at 1.0 mph and 0% inclination. In another 17 patients with intermediate or high exercise tolerance (29 minutes on the modified Bruce protocol), results on the modified Bruce protocol were compared to those obtained with an exercise protocol that was started abruptly at the stage immediately preceding the one in which 1 mm ST segment depression occurred during the modified Bruce protocol.
--.__Varinble angina threshold
September 1989 Heart ~ownal
No. of diseased LYSW~.Y
No
I
Yes No No No Yes
L!
No Yes No NO Yes
1
‘> :i 2
2
Yes Yes No No NO Yes No NO No Yes No Yes Yes No NO
2 1
R, rest.
Exercise tests were performed on consecutive days and their sequence was randomized; before each test at least I hour of complete rest was allowed. One week later all patients underwent a control exercise test while they were not receiving treatment (with the modified Bruce protocol), which was repeated 2 hours later immediately after the administration of 0.5 mg of sublingual nitroglycerin. Exercise testing. Results of 12-lead ECG and blood pressure monitoring (cuff sphygmomanometer) were recorded during the control period and at l-minute intervals during exercise and for 6 minutes during recovery. The level of the ST segment 80 msec after the J point was calculated after signal averaging by a computer-assisted system (CASE, Marquette 12, Marquette Electronics Inc., Milwaukee, Wise.) in all 12 leads. The calculated values were printed out, along with the heart rate, against time in trend format. The ECG lead showing the greatest ST segment depression was selected for analysis. For each test, heart rate and heart rate-systolic blood pressure product at 1 mm ST segment depression were measured. Cardiac catheterization. Selective coronary arteriography was performed in all patients within 6 months of the exercise study by means of the Judkins technique. In 12
Volume
118
Number
3
Exercise type and ischemic threshold
p
Group
p=Ns
I
I
1
I
MB
W
MB
A
1. Effects of warm-up and abrupt exercise on ratepressure product at 1 mm ST segment depression in responders(0) and nonresponders(0). A, abrupt exercise; MB, modified Bruce protocol; W, warm-up exercise. Fig.
patients, after diagnostic angiography, an appropriate view of the most severestenosiswasselectedand mantained for subsequentarteriography. After a control arteriography each patient performed 2 minutes of sustained isometric handgrip exercise at two thirds of a predetermined maximum grip strength with a commercially available device (Stoelting, Inc., Chicago, Il.). Coronary arteriography was repeated immediately after cessationof handgrip exercise. After 10 minutes intracoronary isosorbidedinitrate (2 mg) wasadministered and coronary arteriography repeated. In 11other patients the effect of intracoronary isosorbideonly was assessed. Control coronary arteriograms and those obtained after handgrip exercise and isosorbidedinitrate were analyzed by two independent observers. Coronary artery luminal diameters at the site of the stenosisand of the closestangiographically normal segmentwere measuredby an automated edge contour detection computer analysis system (Computerized Angiographic Analysis System, Pie Medical, Neptune, N.J.). The size of the stem of the Judkins catheter wasusedfor calibration to absolutemeasurement units in millimeters, and correction was made for radiographic pincushion distortion. Data analysis. Statistical analysis was performed by Student’s t test for paired and unpaired data asappropriate. A value of p < 0.05 wasconsideredstatistically significant. RESULTS Effect of different
types of exercise. The heart rate at 1 mm ST segment depression increased from 113 + 13 beats/min (mean k SD) during the stan-
dard modified Bruce exercise test to 119 + 15 beats/ min 0, < 0.05) when the modified Bruce protocol was preceded by a lo-minute warm-up period. The ratepressure product at 1 mm ST segment depression also increased from 18,813 Jo 3682 beats/min x mm
I
MB
in CAD
I
Group II
p c 0.001
p <0.05
I
NTG
I
MB
54 I
I
NTG
2. Effects of sublingual administration of 0.5 mg nitroglycerin on rate-pressureproduct at 1 mm ST segment depressionin groupsI and II. MB, modified Bruce protocol with no treatment; NTG, modified Bruce protocol with 0.5 mg sublingual nitroglycerin. Fig.
Hg to 20,357 k 4227 beats/min X mm Hg 03 < 0.01) (Fig. 1). Analysis of results in individual patients showed that after warm-up in 8 of the 16 patients rate-pressure product at 1 mm ST segment depression increased by at least 2000 beats/min X mm Hg. In these patients heart rate and rate-pressure product at 1 mm ST segment depression increased from 115 + 13 beats/min to 130 f 8 beats/min and from 18,978 + 3318 beats/min X mm Hg to 22,135 f 3301 beats/min X mm Hg, respectively. In the remaining eight patients warm-up resulted in little or no change in heart rate or rate-pressure product at 1 mm ST segment depression (from 111 + 14 beats/min to 109 f 14 beats/min and from
18,648 -t 4241 beats/min X mm Hg to 18,579 +- 4491 beats/min X mm Hg, respectively. The abrupt start exercise on average did not result in significant changes in heart rate (from 129 + 19 beats/min to 128 f 16 beats/min; p = NS) or rate-pressure product (from 21,112 +- 3839 beats/min x mm Hg to 20,410 f 3242 beats/min X mm Hg; p = NS) at 1 mm ST segment depression (Fig. 1). However, in 3 of the 17 patients who underwent abrupt exercise testing a decrease ~2000 beats/min X mm Hg of rate-pressure product at 1 mm ST segment depression was noted. Heart rate at 1 mm ST segment depression decreased from 147 + 4 beats/min during the standard modified Bruce protocol to 134 +- 10 beats/min, and rate-pressure product at 1 mm ST segment depression decreased from 25,453 f 2374 beats/min X mm Hg to 21,436 + 4209 beats/min X mm Hg. In the remaining 14 patients the heart rate changed from 125 t 18 beats/min to
542
Pupita et al.
American
Normal segment
Stenotic
Group I
Group II
p < 0.01
p<0.05
Group I
September 1989 Heart Journal
segment Group II p=NS
p
1
B
HG
B
HG
B
HG
B
HG
Fig. 3. Changesin coronary luminal diameter of normal and stenotic segmentsin responseto isometric
handgrip exercise in groups I and II. 3, basal; HG, handgrip.
126 -+ 17 beats/min and the rate-pressure product from 20,182 f 3463 beats/min X mm Hg to 20,190 + 3149 beats/min X mm Hg. Therefore of the 33 patients included in the study, 11 showed changes in ischemic threshold 22000 beats x mm Hg in response to different types of exercise (variable threshold, group I), whereas the other 22 had little change in threshold (fixed threshold, group II). Reproducibility of results during exercise testing. For each individual patient the results obtained during the two exercise tests performed while patients were not receiving treatment with the modified Bruce protocol were compared. Differences between tests results in heart rate and rate-pressure product achieved at 1 mm ST segment depression were 6.1 f 4.2 beats/min (range 0 to 12) and 994 * 599 beats/min X mm Hg (range 0 to 1850), respectively. In none of the patients was a difference ~2000 beats/min X mm Hg in rate-pressure product at 1 mm ST segment depression observed. In group I the difference in heart rate and rate-pressure product at 1 mm STsegment depression between tests (7.5 + 3.2 beats/min and 1270 + 510 beats/min X mm Hg, respectively) was higher than in group II (5.0 + 2.6 beats/min and 855 + 603 beats/min X mm Hg, respectively); this difference, however, did not achieve statistical significance. Effect of acute administration of nitrates. In group I exercise testing after the administration of sublingual nitroglycerin resulted in a marked increase in heart rate (123 f 18 beats/min vs 145 + 19 beats/ min; p < 0.001) and rate-pressure product (20,744 + 4240beats/min X mmHgvs 25,641 + 4547 beats/min X mm Hg; p < 0.001) at 1 mm ST segment depression. In group II sublingual nitroglycerin increased heart rate and rate-pressure product at 1 mm ST segment depression from 120 * 18 beats/min to
128 +- 16 beats/min (p < 0.001) and from 19,624 * 3740 beats/min X mm Hg to 20,689 ~fi 3406 beats/min x mm Hg 0, < 0.05) (Fig. 2). The increase in heart rate and rate-pressure product at 1 mm ST segment depression after sublingual nitroglycerin was significantly greater in group I than in group II (22 ? 8 beats/min vs 8 + 9 beats/min; 4896 + 1998 beatslmin X mm Hg vs 1064 + 2145 beats/min x mm Hg, respectively; all p < 0.01). Furthermore, in all patients in group I sublingual nitroglycerin increased the rate-pressure product at 1 mm ST segment depression by at least 2000 beats/min x mm Hg, whereas this occurred in only four patients in group II. Angiographic data. The effect of isometric handgrip exercise was assessed in five patients in group I and seven patients in group II; the effect of intracoronary isosorbide dinitrate was evaluated in seven patients in group I and 16 patients in group II. In both groups handgrip exercise resulted in a significant and comparable increase in heart rate (from 72 + 16 beats/min to 95 +- 21 beats/min in group I and from 68 * 12 beats/min to 91 + 18 beatslmin in group II; both p < 0.01) and systolic blood pressure (from 140 + 27 to 172 f 32 mm Hg in group I and from 136 + 19 to 168 -+ 23 mm Hg in group II; both p < 0.01). In none of the patients did angina or ST segment changes develop during handgrip exercise. After handgrip exercise the diameter of the normal segment decreased significantly and to a comparable extent in both groups (from 2.89 -t 1.37 mm to 2.72 + 1.36 mm in group I and from 2.36 ? 0.41 mm to 2.27 * 0.35 mm in group II; p < 0.01 and CO.05, respectively). Similarly, intracoronary isosorbide dinitrate caused a significant increase in the diameter ofthenormalsegmentin bothgroups (from2.9 + 1.13 mmto3.16 f 1.05mmingroupIandfrom2.83 & 0.62
Volume Number
118 3
Exercise type and ischemic threshold in CAD Stenotic segment
Normal segment
6
543
Group I
Group II
pco.05
p-co.05
Group I
Group II p =0.053
2.5
1 /I
0.5 -
1’
I 0
ISDN
I
I
B
ISDN
O-
I B
I
I
1
ISDN
B
ISDN
Fig. 4. Changesin coronary luminal diameter of normal and stenotic segmentsin responseto 2 mg intra-
coronary isosorbidedinitrate in groups I and II. B, basal;ISDN, isosorbidedinitrate. mm to 3.04 it 0.59 mm in group II; both p < 0.05)
(Fig. 3 and 4). After handgrip exercise the diameter of the stenotic segment decreased significantly in group I (from 1.22 + 0.39 mm to 0.99 -t 0.35 mm; p < 0.01) but not in group II (from 1.12 + 0.22 mm to 1.16 f 0.30 mm; p = NS). In group I there was a significant increase in the diameter of the stenosis after intracoronary isosorbide dinitrate (from 1.16 + 0.33 mm to 1.52 2 0.39; p < O.OOl), whereas in group II changes were smaller (from 1.25 + 0.33 mm to 1.36 -t 0.39 mm, p = 0.053) (Figs. 3 and 4). DISCUSSION
The results of this study show that ischemic threshold, assessed by rate-pressure product at 1 mm of ST segment depression, varies depending on the type of exercise performed in a sizable proportion of patients. Whereas the inclusion of a warm-up period tends to increase the ischemic threshold, an abrupt start of the effort can decrease it. These changes were observed in about one third of the patients included in the study, and the magnitude of changes in ischemic threshold observed with different types of exercise was significantly greater than the spontaneous variations observed in the same patients during control exercise tests. To date only a few studies have approached the problem of the relationship between type of exercise and variability of ischemic threshold. Twenty years ago MacAlpin and Kattusl reported that warm-up resulting from a previous exercise improved exercise tolerance in some patients with coronary artery disease. More recently, Jaffe and Quinn4 observed less ECG evidence of ischemia in 21 of 22 patients during
the second of two bicycle exercise tests when the second test had been preceded by a 30-minute warm-up period. Along these lines Garber et a1.5 observed that by performing a submaximal steady-state exercise test at 70% of the peak heart rate achieved with a standard Bruce protocol, patients had a lower ischemic threshold than during the control exercise. Opposite results were obtained by Redwood et al.,6 who did not show significant changes in angina threshold in response to different exercise protocols; however, that report did not provide objective measurements of ischemic threshold and data regarding individual patients were not shown. Although in the present study we do not provide direct evidence of the mechanism responsible for changes in ischemic threshold observed with different types of exercise, our findings indicate that the presence of dynamic stenosis could have played an important role. This view is supported by the fact that during different types of exercise significantly different rate-pressure products (a reliable index of myocardial oxygen consumption7) were achieved at similar levels of ischemia. This is also consistent with the findings of Jaffe and Quinn,4 who observed less ECG evidence of ischemia despite similar workloads when the exercise had been preceded by a warm-up period. A decreased contractility resulting from consecutive testing, as suggested by Williams et al.,8 is a very unlikely explanation in our patients, because exercise tests were performed on different days and in random order. Furthermore, a decreased contractility would not explain the reduction in ischemic threshold observed when the exercise was started abruptly. Although, as hypothesized by Rutenberg,g it cannot be ruled out that changes in preload or in
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peripheral vascular resistance might be responsible for the “warm-up phenomenon,” various lines of evidence indicate that changes in ischemic threshold in these patients were due to dynamic changes in core.nary vasomotor tone at the site of the stenosis. Indeed all patients in whom changes related to the type of exercise were observed had a marked improvement in exercise capacity with sublingual nitrates, a phenomenon that has been shown to be related to a reduced coronary tone at the site of the stenosis.10-13 Furthermore, the administration of intracoronary nitrates in these patients resulted in a significant dilatation of the luminal diameter of the stenosis, whereas isometric handgrip exercise caused significant coronary constriction as also observed by otherP14; it is remarkable that this was observed only in patients in group I and not in patients in group II. Thus ischemic threshold can vary in patients with chronic stable angina in response to different types of exercise. This occurs mainly in patients with the potential for dynamic stenosis; in these patients it appears reasonable to postulate that different types of effort might have a different capacity for affecting coronary tone at the site of critical stenosis. REFERENCES
1. MacAlpin RN, Kattus AA. Adaptation to exercise in angina pectoris. The electrocardiogram.during treadmill walking and coronary angiographic findings. Circulation 1966;33:183-201. 2. Deanfield JE, Maseri A, Selwyn AP, Ribeiro P, Chierchia S, Kirkler S, Morgan M. Myocardial ischemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;2:753-8.
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September 1989 Heart Journal
3. Crea F, Margonato A, Kaski JC, Rodriguez Plaza 1,. Meran DO, Davies G, Chierchia S, Maseri A. Variability of result,s during repeat exercise stress testing in patients with stable angina pectoris: role of dynamic coronary flow reserve. Ai~l HEART
J 1986;112:249-54.
4. Jaffe MD, Quinn NK. Warm-up phenomenon in angina pectoris. Lancet 1.980;2:934-6. 5. Garber CE, Warren LS, Hanna G, Carleton RA, Heller GV. Does exercise intensity influence the ischemic threshold? .JAm Co11 Cardiol 1988;11:24A. 6. Redwood DR, Rosing DR, Goldstein RE, Beiser GD, Epstein SE. Importance of the design of an exercise protocol in the evaluation of patients with angina pectoris. Circulation 1971: 43:618-28. 7. Sheffield LY. Exercise stress testing. In: Braunwald E, ed. Heart disease. Philadelphia: WB Saunders, 1984258-78. 8. Williams DO, Bass TA, Gewirtz H, Most AS. Adaptation to the stress of tachycardia in patients with coronary artery disease: insight into the mechanism of the warm-up phenomenon. Circulation 1985;71:687-92. 9. Rutenberg HL. Of pre-loads, afterload and warm-ups [Letter 1. Lancet 1981;1:272. 10. Kaski JC, Rodriguez Plaza L, Meran DO, Araujo L, Chierchia S, Maseri A. Improved coronary supply: prevailing mechanism of action of nitrates in chronic stable angina. AM HEART J 1985;110:238-45. 11. Brown BG, Bolson E, Peterson RB, Pierce CD, Dodge HT. The mechanism of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. Circulation 1981; 64:1089-97. 12. Brown BG, Lee AB, Bolson E, Dodge HT. Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation 1984;70:18-24. 13. Gage JE, Hess OM, Murakami T, Ritter M, Grimm J, Krayenbuehl HP. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986;73:865-76. 14. Matsuda Y, Ogawa H, Moritani K, Fujii T, Yoshino F, Katayama K, Miura T, Toma Y, Matsuda M, Kusukawa R. Coronary angiography during exercise-induced angina with ECG changes. AM HEART J 1984;108:959-66.