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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:M124-M129 (2000)
© 2000 The Gerontological Society of America

"Warm-Up" Phenomenon in Adult and Elderly Patients With Coronary Artery Disease

Further Evidence of the Loss of "Ischemic Preconditioning" in the Aging Heart

Giancarlo Longobardia, Pasquale Abeteb, Nicola Ferraraa,c, Antimo Papaa, Renato Rosielloa, Giuseppe Furgia, Claudio Calabreseb, Francesco Cacciatoreb and Franco Rengoa,b

a Fondazione "Salvatore Maugeri"–IRCCS, Centro Medico di Telese Terme, Benevento, Italy
b Cattedra di Geriatria, Università degli Studi di Napoli "Federico II," Napoli, Italy
c Dipartimento di Geriatria, Seconda Università di Napoli, Italy

Giancarlo Longobardi, Fondazione \|[ldquo ]\|Salvatore Maugeri\|[rdquo ]\|\|[ndash ]\|IRCCS, Centro Medico di Telese Terme, Benevento, Via Bagni Vecchi, Telese Terme, 82037 Benevento, Italy E-mail: glongobardi{at}fsm.it.

Decision Editor: William B. Ershler, MD


   Abstract
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 Abstract
Methods
 Results
 Discussion
 Conclusions and Clinical...
 References
 
Background. A reduction of exercise-induced ischemia in patients with coronary artery disease by means of brief period of exercise followed by resting is called the "warm-up" phenomenon. This phenomenon may represent a clinical counterpart of "ischemic preconditioning." We studied the warm-up phenomenon in both adult and elderly patients with similar angiographic evidence of coronary artery disease, using three exercise tests after excluding the "training effect."

Methods. In order to verify the presence of "training effect," three exercise tests were performed in days 1, 2, and 3 ("training" tests). The third test was used as baseline for a successive test, performed after a recovery period of 10 minutes to reestablish baseline electrocardiographic conditions. A third exercise test was performed 30 minutes later ("warm-up" tests).

Results. "Training" tests did not differ in all parameters in both adult and elderly patients. "Warm-up" tests showed that time to onset 1-mm ST depression was significantly higher (p < .001), whereas ST depression and time to recovery was significantly lower in the second and third test in adult but not in elderly patients ( p < .001). Difference (in seconds) in the time at which 1-mm ST depression occurred on first warm-up exercise compared with the second was inversely correlated with age (p < .001).

Conclusions. Previous exercise followed by resting is able to reduce the successive exercise-induced ischemia ("warm-up" phenomenon) in adult but not in elderly patients with coronary artery disease. This is independent of a greater age-related severity of coronary disease and of "training effect." These results confirm the hypothetical age-related reduction of "ischemic preconditioning" in aging heart.

THE severity of coronary artery disease increases progressively with age. Acute myocardial infarction in elderly persons is associated with a poor short-term prognosis and a high mortality rate (1)(2). Whether previous ischemic episodes are correlated with an age-related increased risk of mortality is controversial (3).

Exercise-induced ischemia in patients with coronary artery disease is paradoxically reduced by a previous brief period of exercise followed by resting; this phenomenon has been called "warm-up" (4)(5). Improved performance following a first exercise test has recently been confirmed in patients with chronic stable angina (6)(7)(8). A reduction in electrocardiographic signs of ischemia in a second bicycle exercise test was first observed by Jaffe and Quinn, who suggested coronary vasodilatation as a possible explanation for the increased tolerance to myocardial ischemia (6). But other authors have suggested that this adaptation to myocardial ischemia is related to a decrease in myocardial oxygen consumption (9)(10) or to a slower increase of cardiac work-load (similar to that observed during training) (11).

More recently, the warm-up phenomenon has been attributed to an endogenous form of myocardial protection, known as ischemic preconditioning (12). Murry and colleagues have demonstrated that brief repeated episodes of ischemia make the heart more resistant to a successive prolonged insult (13). Coronary angioplasty (14), preinfarction angina (15), and the warm-up phenomenon (12) are commonly defined as clinical counterparts of "ischemic preconditioning." In this regard, we have recently demonstrated an age-related reduction of "ischemic preconditioning" at both experimental and clinical level (16)(17).

The aim of this study is to investigate "warm-up" phenomenon in both adult and elderly patients with chronic stable angina by using three exercise tests after excluding the hypothetical "training effect."


   Methods
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 Abstract
 Methods
Results
 Discussion
 Conclusions and Clinical...
 References
 
Patient Groups
We studied 36 patients with chronic stable angina (symptom duration ranging from 6 to 48 months). Of these, 18 were <65 years old (15 men and 3 women; mean age 55 ± 6) (adult group) and 15 >=65 years old (12 men and 3 women; mean age 73 ± 5) (elderly group). All patients had reproducible positive exercise test for myocardial ischemia with horizontal downsloping ST-segment >1 mm. All patients had at least one critical stenosis (internal diameter reduction >70%) in the proximal two thirds of one major epicardial coronary artery. No significant differences in angiographic findings were found between the adult and elderly groups (see Table 1 ). All patients were normotensive in sinus rhythm and without evidence of left ventricular hypertrophy or conduction defects, which could interfere with the interpretation of ST-segment changes. There was no evidence of previous myocardial infarction, heart failure, cardiomiopathy or valvular disease in both groups. No patient was taking digitalis. Nitrate preparations and calcium entry blocking agents were withdrawn 4 days before the study and ß-blockers 2 weeks before. Only sublingual nitroglycerine was permitted subsequently, and, if this drug was used, the test was initiated at least 12 hours after its consumption. The institutional ethics committee approved the study and all patients gave informed consent.


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  		Table 1. Coronary Angiographic Findings in Adult and Elderly Patients

 
Exercise Test
Computer-assisted bicycle exercise tests were performed using the Bruce protocol. All exercise tests were performed between 09.00 and 12.00 hour in a thermostatically controlled room. A standard 12-lead electrocardiogram and arterial blood pressure (cuff sphygmomanometer/noninvasive finger blood pressure monitor based on the Penatz method (Ohmeda 2300 Finapress BP monitor, Englewood, CO) were obtained in a standing position at baseline; at 1-minute intervals during exercise and at peak exercise; up to 10 minutes after exercise; and at 1.0 mm ST-segment depression, at the onset of angina, and when clinically indicated. Three electrocardiographic leads were continuously monitored before, during, and after exercise, and up-to-date QRS complexes of all electrocardiographic leads were continuously displayed on screen. The level of the ST-segment, 80 ms after the J point, was calculated after signal averaging by means of a computer-assisted system (Case Marquette 15, Electronics Inc., Milwaukee, WI) in all 12 leads. The calculated values were printed out, along with the heart rate, against time in trend format; measurement of the ST-segment level was accurate to 0.1 mm. Myocardial ischemia was diagnosed when a horizontal or downsloping ST-segment depression of 1 mm at 80 ms from the J point was observed in at least one lead. The electrocardiographic strips of all tests were evaluated independently in a blind fashion by two cardiologists; in case of disagreement, the matter was resolved by consensus.

Criteria for interrupting the test were the following: ST-segment depression >=2 mm, maximal age-related heart rate, severe chest pain, physical exhaustion, and occurrence of other harmful conditions such as hypotension, severe arrhythmia, and dyspnea. At the beginning of each exercise test patients were instructed to promptly report the onset of anginal pain. Experienced cardiologists examined the tests per group of five patients (25 tests) in a blinded fashion. The following parameters were measured: resting heart rate and blood pressure; time (in seconds) to the onset of 1.0-mm ST-segment depression; heart rate, blood pressure, and heart rate–blood pressure product (heart rate x systolic blood pressure) at each minute of exercise, and at the onset of 1.0 mm ST-segment depression; maximal ST-segment depression; metabolic equivalents of oxygen consumption at the onset of 1-mm ST-segment depression and at peak of exercise; exercise duration, in seconds; time to the recovery of ST-segment depression, in seconds; time to pain onset, in seconds.

Exercise Protocol
To attenuate the "training effect," an exercise test was performed on days 1, 2, and 3 ("training" tests). Three adult patients showing a variation in exercise duration more than 15% among the first three exercise tests were excluded. In order to verify the hypothetical improvement in ischemic parameters, the third test was used as baseline for a successive test, performed after a recovery period of 10 minutes to reestablish baseline electrocardiographic conditions. A third exercise test was performed 30 minutes later. The exercise tests on day 3 were defined as "warm-up" tests.

Statistical Analysis
Angiographic coronary findings were analyzed by using the Fisher's exact test. Two-way analysis of variance (ANOVA) for repeated measures was used to compare hemodynamic and electrocardiographic data during repeated exercise test between the adult and elderly groups. If the F ratios were significant, post hoc Scheffé's test was applied to assess significance. Data were expressed as mean ± SD, unless otherwise indicated. Correlation analysis was performed by comparing the difference (in seconds) in the time at which 1-mm ST depression occurred on the first warm-up exercise, compared to the second stratified by age. p < .05 was considered significant.


   Results
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Discussion
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The results of repeated exercise test on days 1, 2, and 3 (so-called "training" tests) are shown in Table 2 . The tests did not differ in any parameter, demonstrating the absence of training effect in both adult and elderly patients. However, in all three tests there was a difference in exercise duration between adult and elderly patients.


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  		Table 2. Results of Repeated Exercises ("Training" Tests) in Adult and Elderly Patients

 
Hemodynamic data of the "warm-up" tests are shown in Table 3 . At baseline, heart rate and rate-pressure product were higher at the second test with respect to first and third tests in adult (p < .001) and only heart rate in elderly patients (p < .001); heart rate, but not systolic blood pressure and rate-pressure product at baseline, was also different in elderly patients (p < .05). In both adult and elderly patients, at 1-mm ST depression and at peak exercise, there were no differences among the three tests in heart rate, systolic blood pressure and rate-pressure product. Time to onset 1-mm ST-depression was significantly higher in the second and third tests with respect to the first one in adult (from 434 ± 154 to 557 ± 159 and 542 ± 150 s, respectively) but not in elderly patients (from 304 ± 40 to 300 ± 62 and 300 ± 68 s, respectively); in all three tests this parameter was significantly lower in elderly than in adult patients (p < .001) (Fig. 1). ST-depression at peak was significantly lower in the second and third tests than in the first one in adult (from 1.9 ± 0.5 to 1.2 ± 0.6 and 1.0 ± 0.4 mm, respectively) but not in elderly patients (from 1.8 ± 0.6 to 1.7 ± 0.5 and 1.9 ± 0.7 mm, respectively); this parameter was significantly higher in the second and third tests in elderly with respect to adult patients (p < .001) (Fig. 1). Finally, time to recovery was significantly lower in the second and third tests with respect to the first one in adult (from 188 ± 75 to 78 ± 59 and 100 ± 45 s, respectively), but not in elderly patients (from 270 ± 93 to 300 ± 11 and 312 ± 126 s, respectively); in all three tests this parameter was significantly higher in elderly with respect to adult patients (p < .001) (Fig. 1). More importantly, correlation analysis demonstrates that the difference (in seconds) in the time at which 1-mm ST depression occurred on the first warm-up exercise compared to the second was inversely correlated with age (p < .001) (Fig. 2).


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  		Table 3. Hemodynamic Data During Repeated Exercises ("Warm-Up" Tests) in Adult and Elderly Patients

 


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  		Figure 1. 1-mm ST onset (panel A), ST depression (panel B), and ST recovery (panel C) in adult and elderly patients with coronary artery disease in Tests 1, 2, and 3 of the "warm-up" tests (*p < .001 vs Test 1).

 


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  		Figure 2. Correlation analysis between the difference (in seconds) of the time at which 1-mm ST depression occurs on first compared to second "warm up" test ({Delta} Onset 1-mm ST depression) and age.

 
Interestingly, exercise duration and maximal work load did not change during the three tests in adult patients, whereas in elderly patients both parameters significantly increased in the second and third tests with respect to the first test; yet, both exercise duration and maximal work load significantly differed between adult and elderly patients in all three tests (Table 4 ).


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  		Table 4. Exercise Duration (ED) and Maximal Work Load (MWL) During Repeated Exercises ("Warm-Up" Tests) in Adult and Elderly Patients

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Conclusions and Clinical...
 References
 
The present study demonstrates that previous exercise followed by resting is able to reduce the successive exercise-induced ischemia ("warm-up" phenomenon) in adult but not in elderly patients with coronary artery disease. Myocardial ischemic parameters (time to onset 1-mm ST-segment depression, ST-segment depression, and time to recovery) significantly improved during the second exercise test only in adult patients. Finally, difference (in seconds) in the time at which 1-mm ST depression occurs on first warm-up exercise compared to the second was inversely correlated with age. This phenomenon was independent of a greater age-related severity of coronary disease and of "training effect" as demonstrated by the absence of parameter modification among the exercise tests performed on 3 consecutive days before the study day.

Age-Related Severity of Coronary Artery Disease
Coronary artery disease in the elderly is associated with both poor prognosis and a high mortality rate in the years after the initial events (1)(2). In the United States, in fact, deaths from ischemic heart disease occur in about 80% of patients over age 65. However, whether this age-related increase of poor prognosis is associated with a more severe coronary atherosclerosis is unclear. Coronary atherosclerosis extends progressively with age but the number of lesions is similar in both men and women after 60 years of age as demonstrated in postmortem examination studies (18)(19). Acute myocardial infarction is very frequently the first manifestation of coronary artery disease regardless of age and severity of coronary stenosis (20). Furthermore, as Maggioni and colleagues have demonstrated (1), in patients with ST-segment elevation and fatal myocardial infarction, the degree of critical coronary stenoses is not age-related. Accordingly, in our study the absence of "warm-up" phenomenon in elderly patients was not associated with a greater severity of angiographic coronary stenoses. Consequently, the absence of this phenomenon in elderly patients may not be related to a more extensive coronary artery disease but to a reduction of an unknown endogenous protective mechanism.

"Warm-Up" Phenomenon
The term "warm-up" refers to the phenomenon when a patient who stops exercise because of angina can resume exercise without developing further angina after resting. This phenomenon was first demonstrated by Kemball Price over 40 years ago (5). Jaffe and Quinn (6) demonstrated in 34 patients with angina pectoris a significant reduction in maximum ST depression in a second exercise test performed 30 minutes after a first test, and suggested a coronary vasodilatory effect as a possible mechanism of the "warm-up" phenomenon. Okazaki and colleagues performed two consecutive exercise tests with an interval of 15 minutes and found a significant ST-segment depression associated with an attenuated increase in regional oxygen consumption in the absence of increased coronary flow (10). Successively, Tomai (7) and Maybaum (8) and their colleagues confirmed these findings by two consecutive treadmill exercise tests with a recovery interval.

"Training Effect"
Moreover, "warm-up" phenomenon studies were probably affected by the so-called "training effect." Exercise training has been demonstrated to diminish exercise-induced ST-segment abnormalities either by improving coronary blood flow or developing collateral circulation, or improving oxygen extraction and utilization by the heart (21)(22). More recently, Maybaum and colleagues (8) performed three exercise tests on consecutive days before the "warm-up" protocol in order to eliminate this variable. The absence of improvement in the ischemic parameters among these three tests suggests that the protective effect of "warm-up" is independent of "training effect." In our study using the protocol of Maybaum and colleagues (8), exercise duration and maximal workload did not vary among the three "training" tests in adult and elderly patients, but we observed an improvement of maximal workload and exercise duration during the three "warm-up" tests only in elderly patients. The mechanism of this phenomenon is unclear. One hypothesis could be an acute recruitment of collateral vessels that are probably more developed in elderly patients given the chronic nature of the disease (23). Nevertheless, the absence of "warm-up" phenomenon in elderly patients is further evidence that it is independent of the presence of collateral coronary flow.

"Ischemic Preconditioning"
In 1986 Murry and colleagues (13) called "ischemic preconditioning" the phenomenon in which brief episodes of ischemia and reperfusion protect the myocardium from a more prolonged episode of ischemia. The mechanism behind this phenomenon is probably related to activation of protein kinase C by stimulation of several substances such as norepinephrine, adenosine, bradykinin, and opioid receptors (24). Coronary angioplasty (14) and preinfarction angina (15), and recently also the warm-up phenomenon, has been considered as a clinical manifestation of ischemic preconditioning (12). In particular, the relationship between "warm-up" phenomenon and "ischemic preconditioning" is strongly supported by invasive investigations. Williams and colleagues (9) studied 11 patients with stable angina caused by a stenosis of left descending coronary artery. In order to increase the oxygen demand, atrial pacing was performed twice with an interval of 5–10 minutes; during the second pacing, ST-segment depression, myocardial blood flow, and oxygen consumption were reduced. These observations exclude collateral flow as the mechanism of "warm-up" phenomenon. Okazaki and colleagues (10) reported the same findings in 13 patients with left anterior descending stenosis by performing two exercise tests separated by 15 minutes of rest. In addition, they found that adenosine production was enhanced in the ischemic region on the second exercise test. These results strongly indicate that the "warm-up" phenomenon is an adaptive mechanism as is ischemic preconditioning.

Recently, it has been experimentally demonstrated that ischemic preconditioning is absent in aging heart, suggesting that a reduction of norepinephrine release after transient ischemic stimulus is responsible for the age-related loss of this adaptive mechanism. Exogenous administration of norepinephrine, in fact, is able to mimic ischemic preconditioning in senescent hearts (17). The reduction of "ischemic preconditioning" was subsequently confirmed by Tani and colleagues, who suggest an alteration of ryanodine-sensitive sarcoplasmic reticulum Ca2+ release to explain this phenomenon (25). Clinically, preinfarction angina seems to lose its protective role in elderly patients with acute myocardial infarction (18). The presence or absence of angina before acute myocardial infarction reduces the incidence of in-hospital death, congestive heart failure, shock, and the combined end-points in adult but not in elderly patients; logistic regression analysis for these in-hospital end-points indicate that preinfarction angina plays a protective role only in adult patients with acute myocardial infarction (18).

Elderly patients are present in some study populations where "warm-up phenomenon" is present. For example, Tomai and colleagues (7) demonstrated a robust "warm-up phenomenon" in patients with a mean age of 61, maximum age 70 years; similarly, Williams and colleagues (9) included patients with an age up to 72 in their study. However, this is not so surprising. We suggest that the potential for ischemic preconditioning could still remain in elderly persons and that the age difference in preconditioning is relative rather than absolute. This possibility is more consistent with most physiologic age-related changes, which vary along a continuum rather than in a "all-versus-none" fashion.


   Conclusions and Clinical Implications
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions and Clinical...
References
 
The present study demonstrates that the "warm-up" phenomenon is reduced in elderly patients regardless of the severity of coronary artery disease and of training effect. These results confirm the hypothesis that the possible absence of protective endogenous mechanism (such as ischemic preconditioning) might explain the poorer prognosis of elderly patients with coronary artery disease. Further studies are necessary in order to find a "preconditioning-mimetic" procedure and/or drug capable of reproducing or restoring this protective mechanism in the aging heart.

Received March 31, 1999

Accepted July 6, 1999


   References
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 Results
 Discussion
 Conclusions and Clinical...
 References
 

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