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Presence of Ischemic Preconditioning
Induced by Exercise in Patients with
Coronary Disease

Álvarez Gómez, J.A.; Rivas Estany, E.;
Stüsser Beltranena, R.J.; Hernández Cañero, A.;
García Barreto, D.; Barrera Sarduy, D.;
Hernández González, R.

Heart Rehabilitation Center, Institute for Cardiology and
Cardiovascular Surgery, Havana, Cuba

SUMMARY
Introduction: Ischemic preconditioning is a cardioprotector feature which depends of methabolic mechanisms.
Objective: This study has the aim to show through the exercise induced ischemia the presence of classic ischemic preconditioning and the second window.
Material y method: Fourteen patients, 9 male and 5 female, with coronary heart disease documented by angiography or myocardial perfusion studies, and a positive exercise test were included. All of them had three consecutive exercise tests (ET I, ET II, y ET III), achieving in them similar individual workloads, with intervals of 30 minutes and 24 hours, respectively, being measured in each test different clinical and EKG variables. Means differences were tested with analysis of variance of repeated measures.
Results: Statistical significant mean differences were found between ET I and II (P=.001) and between ET I y III (P=.05) in the following variables: ischemia duration (434 ± 228, 300 ± 177, 314 ± 226); ST segment depression (-2.9 ± 1.3, -2.1 ± 1.3, -2.2 ± 1.1); variation of the slope of the ST/Heart Rate: (-507 ± 188, -360 ± 225, -402 ± 180); and between ET I and III (P=.05) in the angina duration (243 ± 66, 172 ± 109, 122 ± 90).
Discussion: The statistical significance of our results for the classic phase of preconditioning are almost the same than most of the previous studies, but the significance of the statistical presence in the results of the second window are different than those found by other researches.
Conclusion: As conclusion, this study gives evidence that from an exercise induced ischemia the myocardium can stay preconditioned in the classic phase and during the second window.

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INTRODUCTION
   Ischemic preconditioning is a cardioprotective mechanism demonstrated in animals and in humans. (1-5) The mechanism probably is related to metabolism and not depending on collateral circulation. (6-13) Ischemic preconditioning appears soon after the initial ischemic event and it may diminish but reappear at 24 hours and last between 48 and 72 hours (14).

OBJECTIVE
   The purpose of this investigation was to evaluate the effect of exercise as a preconditioning stimulus at 30 minutes and 24 hours in patients with coronary artery disease

MATERIAL AND METHOD
   Fourteen patients were studied, nine male and five female with a mean age of 60.5 ± 10.5 years. All patients had coronary disease demonstrated by coronary angiography or thallium perfusion study, and all had a positive exercise test, the investigation began fifteen days or more after the initial exercise test to determine the presence of ischemia. No patient had evidence of left ventricular hypertrophy, conduction abnormalities, valvular disease or heart failure. In addition, any electrocardiographic abnormality that would interfere with the interpretation of change of the ST segment excluded patients from the study. No patient took digitalis, nitrates, and calcium antagonists for four days prior to entering the study, and beta blockers in the previous seven days. Patients were allowed to use nitroglycerin sublingually, although the ones that used it in the last 48 hours prior to the investigation were excluded. All patients gave informed consent and the protocol was approved by the Committee of Ethics of the Institute for Cardiology and Cardiovascular Surgery, Havana, Cuba, in accordance with the Declaration of Helsinki.

   All patients had three exercise tests (Erg I, Erg II and Erg III). The exercise protocol consisted of an increase of 25 watts every three minutes with an interval of time of 30 minutes between Erg I and Erg II and 24 hours between Erg I and Erg III. All the exercise tests were carried out between 2 p.m. and 4 p.m. with the temperature in the laboratory between 22 and 24° C. A 12 lead electrocardiogram and blood pressure using a sphygmomanometer were taken in all patients in basal conditions and later at every minute during the exercise and for ten minutes in the recovery phase. Three ECG leads were monitored continually before, during and after exercise and the average QRS complexes of each one of the leads were observed continually on the monitor. The level of the ST segment at 80 milliseconds after the J point was calculated in each one of the 12 leads through an online system (ERGOCID, ICID, Havana, Cuba). Myocardial ischemia was diagnosed when there was 1 mm of ST segment depression downsloping or horizontal 80 milliseconds after the J point (ischemic threshold). Duration of ischemia was measured from the time 1 mm ST depression occurred until there was less than 1 mm ST segment depression. Duration of ST segment depression to recovery to iso-electric baseline after exercise was stopped was also recorded. The magnitude of the ST segment depression at the time of maximum exercise as well as the slope of the ST segment depression / heart rate, (15, 16) was measured by an automated system. The minor or equal values to -140 were considered positive for myocardial ischemia. The double product (DP), heart rate x systolic blood pressure, was measured at the ischemic threshold and at the highest level of ST segment depression during maximum exercise.

   Electrocardiographic changes were assessed in a blinded fashion by two cardiologists and the results are based on their consensus opinion.

   Patients were instructed to report immediately the development of angina as well as the moment of its disappearance and instructed to evaluate the intensity of the angina on a 0 to 10 scale.

   Data in tables I and II are shown as mean and standard deviation as well as median, when they were not adjusted to the normal distribution, previous histogram and Shapiro Wilk's normality test. There were carried out in consequence analysis of variance for one-sample repeated measures and non-parametric of Friedman with the SPSS software (SPSS Inc., Chicago, Ill), as required the parameters in study. A p value < 0.05 was considered a significant difference.




RESULTS
   The mean results of the three exercise tests are reflected in Table I with 14 patients and 7 variables related to the ST segment of the electrocardiogram. Table II summarizes the results in 6 patients with 5 variables related to angina. The onset of the ischemic threshold on the electrocardiogram was prolonged by 43 seconds in Erg II, p < 0.001 and 53 seconds in Erg III; p < 0.001 compared to Erg I. The double product related to the ischemic threshold in Erg II and Erg III were also larger than in Erg I; p > 0.05. (See Table I) The magnitude of ST segment depression during maximum exercise was larger by 0.8 mm in Erg I than in Erg II; p < 0.001, and 0.7 during Erg III; p < 0.05. The difference between Erg II and Erg III was small; p > 0.05. The slope relating ST segment depression to heart rate (ST/HR) was 147 units less in Erg I than in Erg II; p < 0.001 and 105 units less than in Erg III, p < 0.05. The difference was not statistically significant between Erg 1 and Erg III p > 0.05.

   Recovery of the ST segment to iso-electric baseline was 314 seconds later in Erg I than in Erg II; p < 0.001, and 148 seconds later than in Erg III; p < 0.05.

   There was a difference of 166 seconds between Erg II and Erg III; p < 0.05. When median values were considered, there were 180 seconds difference between Erg I and Erg II and between Erg II and Erg III, p < 0.05 but there was no difference between Erg 1 and Erg III, p > 0.05. The duration of ischemia as measured by ST segment depression was 134 seconds larger in Erg I than in Erg II, p < 0.01 and 120 seconds larger than in Erg III, p < 0.05. Between Erg II and Erg III the difference was not statistically significant, p > 0.05.

   All of the differences of the electrocardiographic variables between Erg I and Erg II were larger than in those of Erg I and Erg III.

   Angina appeared 20 seconds earlier in Erg I than in Erg II and was even greater and more significant (50 seconds) between Erg I and Erg III, p < 0.05. (See Table II) The double product related to angina threshold in Erg II and Erg III were slightly larger than in Erg I, but not statistically significant, p > 0.05.

   The mean scores of the self evaluation of the intensity of the angina pain were larger in Erg I (2.3) than in Erg II and Erg III (3.8). This was statistically significant, p < 0.05.

   Angina disappeared 61 and 68 seconds later in Erg I than in Erg II and Erg III, p < 0.05.
The duration of angina was larger in Erg I than in Erg II and III with the major difference being 121 seconds between Erg I and Erg III, p < 0.05.

DISCUSSION
   Repetitive exercise is one clinical model that can be used to assess the adaptation to myocardial ischemia in the human (17-19). Others have reported improvement of ischemic parameters during repeated exercise testing and suggested that this may be a possible model for myocardial preconditioning. The results of our exercise protocol show that there is delay of the ischemic threshold both electrocardiographic and symptomatic, less ST segment depression during maximum exercise, less negativity of the slope of relationship of ST segment depression to heart rate, quicker recovery of the ST segment, earlier relief of angina, and a decreased duration of total ischemic load both electrocardiographic and symptomatic.

   The double product did increase during the second and third exercise testing compared to the first, but this was without statistical significance.

   Williams et al. (20) and Okazaki et al. (21) subjected patients to two stress tests (atrial electrical stimulation and exercise) and measured coronary venous flow. They were able to show that coronary venous flow in the second stress test in relationship to the first one, that there was no increase in coronary sinus flow. Tomai et al. (22) subjected a group of 15 patients to a protocol similar to those of the present study using three serial exercise tests with ten minutes between the first and the second and 24 hours between the second and the third. These investigators reported "cardioprotection" by ischemic preconditioning in the second exercise test, but were unable to confirm this in the third test. They concluded that "cardioprotection" during the third exercise test was more likely due to training linked to a warm-up phenomenon rather than ischemic preconditioning.

   In contrast, the data contained in our report indicate that myocardial oxygen consumption related to the variables was larger in the third test in relationship to the first one, but without statistical significance. Because of this, we are unable to exclude the possibility that ischemic preconditioning induced by exercise serves as a means of "cardioprotection" found at 24 hours.

CONCLUSION
   When ischemia is induced by exercise, there is less evidence of ischemia at 30 minutes and 24 hours. The mechanism maybe related to ischemic preconditioning.

REFERENCES

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15. Berenyi I, Hajduczki IS, Boszormenyi E: Quantitative evaluation of exercise-induced ST-segment depression for estimation of degree of coronary artery disease. Eur Heart J 1984;5:289-294

16. Elamin MS, Boyle R, Kardash MM, Smith DR, Stoker JB, Whitaker W, Mary DA, Linden RJ: Accurate detection of coronary heart disease by new exercise test. Br Heart J 1982;48:311-320

17. Jaffe MD, Quinn NK: Warm-up phenomenon in angina pectoris. Lancet 1980;2:934-936

18. Maybaum S, Ilan M, Mogilevsky J, Tzivoni D: Improvement in ischemic parameters during repeated exercise testing: a possible model for myocardial preconditioning. Am J Cardiol 1996;78:1087-1091

19. Tomai F, Danesi A, Ghini AS, Crea F, Perino M, Gaspardone A, Ruggeri G, Chiariello L, Gioffre PA: Effects of K(ATP) channel blockade by glibenclamide on the warm-up phenomenon. Eur Heart J 1999;20:196-202

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21. Okazaki Y, Kodama K, Sato H, Kitakaze M, Hirayama M, Hori M, Inoue M: Attenuation of increased regional myocardial oxygen consumption during exercise as a major cause of warm-up phenomenon. J Am Coll Cardiol 1993;21:1597-1604

22. Tomai F, Perino M, Ghini AS, Crea F, Gaspardone A, Versaci F, Chiariello L, Gioffre PA: Exercise-induced myocardial ischemia triggers the early phase of preconditioning but not the late phase. Am J Cardiol 1999;83:586-588

 

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
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