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1 COMMENT THIS ARTICLE SEE COMMENTS ON THIS ARTICLE CONTACT AUTHOR December 1998 (Volume 39, Number 4) Two Year Follow-up of Cardiac Mortality and Recurrent Cardiac Events in Patients after Acute Myocardial Infarction or Unstable Angina Katija Èatipoviæ-Veselica, Josip Ðurijanèek, Vjekoslav Amidžiæ, Damir Kozmar, Dinko Buriæ, Brankica Juraniæ Division of Cardiology, Department of Internal Medicine, Osijek University Hospital, Osijek, Croatia Aim. To assess the relation between predischarge heart rate, heart rate variability, left ventricular ejection fraction, cardiac mortality, and recurrent non-fatal cardiac events in a 2-year follow-up of 95 patients after acute myocardial infarction or unstable angina. Methods. Heart rate and heart rate variability were assessed in various portions of a complete 24- hour electrocardiographic recording obtained three weeks after hospital admission. Both the beginning and the length of the analyzed portions varied by 20 minutes (a total of 5,100 RR intervals). Results. During a follow-up period of two or more years, there were 14 cardiac deaths in patients with previous myocardial infarction. Eight patients had recurrent cardiac event and were hospitalized. Twenty-nine patients had an effort-provoked angina. There was a significant positive association between the heart rate and cardiac mortality and significant inverse association between heart rate variability, left ventricular ejection fraction, and cardiac mortality in postinfarction patients. There was no significant difference in heart rate, heart rate variability, and left ventricular ejection fraction between postinfarction patients and patients with unstable angina with or without secondary cardiac events. Conclusion. Changes in the heart rate, heart rate variability, and left ventricular ejection fraction were associated with higher cardiac mortality in postinfarction patients. Secondary non-fatal cardiac events were not associated with these variables in patients after either myocardial infarction or unstable angina. Key words: adrenergic b-antagonists; angina, unstable; electrocardigraphy, ambulatory; heart rate; myocardial infarction; ventricular ejection fraction; streptokinase The relationship between the heart rate and coronary heart disease has been recognized for long time (1-5). Levy et al (6) were the first to report an association between tachycardia and cardiovascular death in general. This finding was confirmed by later studies (7-10). There is a general agreement that the heart rate is a strong determinant of life prognosis because the total mortality appeared definitely higher among subjects with higher resting heart rates (6,11). Autonomic dysfunction plays an important role in the development and progression of many cardiovascular disorders. During recent years, analysis of the heart rate variability has evolved as a non-invasive tool to provide insight into autonomic control of the heart. Cardiac responses to sympathetic stimulation have a slow onset and also terminate relatively slowly. In contrast, vagal effects on the heart have a rapid onset and also rapidly disappear. Vagal activity may therefore allow for a rapid, beat-to-beat modulation of the heart rate. The reduction in the heart rate variability correlates with the risk of death. In coronary artery dissease heart rate variability is also reduced, roughly in proportion to the extent of the disease (12). Reduced heart rate variability in patients after myocardial infarction signals an increased risk of death, especially sudden death due to arrhythmic events (13). The aim of our study was to assess the relation between 24-hour mean RR interval (heart rate), and 24-hour standard deviation of the mean RR interval (heart rate variability) computed from predischarge 24-hour Holter recordings, as well as left ventricular ejection fraction and cardiac mortality or recurrent cardiac events in a 2-year follow-up of the patients who suffered acute myocardial infarction or an episode of unstable angina. Patients and Methods The study group included 95 patients admitted to our hospital because of acute myocardial infarction (AMI) and unstable angina pectoris, who had completed a 2-year follow-up after an acute myocardial infarction (N=71) or episode of unstable angina (N=24). The patients were less than 70 years old. Acute myocardial infarction was diagnosed when two out of three criteria were met: chest pain of ischemic type lasting ³20 min, an increase and decrease in plasma concentration of creatine kinase concentration with a peak at least twice the upper limit of the reference range of our laboratory, and

2 the development of a new pathologic Q wave or ST-T changes suggestive for a non-q-wave infarction (14). Unstable angina was defined as the presence of at least one episode of angina at rest within previous 48 hours, with either documented transient electrocardiographic (ECG) changes during chest pain or persistent ECG changes compared to a recent (1 month) electrocardiogram (15). Fortythree patients received atenolol. Atenolol was administered to both the patients with myocardial infarction (50 mg/day) and those with unstable angina (100 mg/day). The treatment was initiated after the admission to the coronary care unit and continued during the follow-up. Five patients received streptokinase ( U over 60 minutes) within 6 hours of the onset of symptoms. All patients were given aspirin (100 mg/day) during hospitalization and follow-up. Nitrates were administered to the 98% of all the patients during the hospitalization and to 79% of them during the follow-up. Angiotensin converting enzyme (ACE) inhibitors were administered to 9% of patients during hospitalization and to 24% during follow-up. None of the patients received calcium antagonists. Patients with a serious non-cardiac or non-ischemic cardiac disease, history of cardiac surgery, permanent pacemaker, atrial fibrillation, flutter or any other sustained rhythm disturbance, conduction system abnormalities, autonomic neuropathy, treatment with antiarrhythmic agents or those who refused or were unavaibile for the follow up were excluded from the study. Noninvasive cardiac evaluation by means of M-mode and 2-dimensional echocardiography was performed in all patients before the hospital discharge. M-mode and 2-dimensional echocardiography was performed with a ultrasonic instrument (Toshiba, Otawara, Japan) using a 3.5 MHz transducer. Left ventricular ejection fraction was determined by usual echocardiography (16). Measurement of Heart Rate Variability Two-channel 24-hour electrocardiographic recordings (modified lead III and modified chest lead V5) using a Siemens recorder (Erlangen, Germany) were obtained in the third week (15-18 days) after hospital admission. For each patient, heart rate and heart rate variability were measured in different portions of a complete 24-hour recording, whose beginning and duration varied. The onset of the analyzed portions varied by 20 minutes (72 values, ranging from 00:00 to 23:40) and the duration of the analyzed portions also varied by 20 minutes (72 values, ranging from 20 minutes to 24 hours). In total, 5, hour intervals were analyzed. Where the analyzed interval involved a physical end of the recording, 24-hour electrocardiogram was recorded as a continuous loop i.e., the end of the recording was extended with the properly timed beginning of the recording from the previous day (17). For each interval analyzed, the duration of normal-to-normal RR interval was measured manually, and the mean duration of RR intervals was computed. Heart rate variability was expressed by the standard deviation of RR interval duration for the entire 24-hour (18). During the first 2-year follow-up, there were 14 cardiac and 1 non-cardiac death among the patients with previous myocardial infarction. Eight patients had recurrent cardiac events and were hospitalized: 5 patients because of unstable angina, 2 underwent surgical revascularization, and 1 patient suffered reinfarction. Twenty-one patients had an effort-induced angina according to the Rose questionnaire for angina pectoris (19). Statistical Analysis Nonparametric Mann-Whitney s test was used to compare the data between patients subgroups (survivors vs. nonsurvivors, secondary cardiac events vs. no such events). Comparison of the number of patients with a certain clinical characteristic were performed using the chi-square test. The impact of the heart rate, heart rate variability, and left ventricular ejection fraction determined at the hospital discharge on cardiac mortality was studied with univariate logistic regression analysis. Statistical package SPSS 5.0 was used for the analysis. A p<0.05 value was considered statistically significant. Results Clinical characteristics of the patients are shown in 1. There were no significant differences among these three groups the in age, sex, localization of infarction, previous myocardial infarction, previous unstable angina (p=0.09), or in the proportion that received b-blockers and trombolysis treatment (p=0.25). Secondary cardiac events were more frequent in patients with previous unstable angina (50%) than in the patients with previous myocardial infarction (29%; p=0.03). During the follow-up period of ³2 years (median 2.4 years, range 2-4 years), there were 14 cardiac deaths in the patients with previous myocardial infarction. There was a significant difference in the mean RR interval, mean standard deviation of RR intervals duration, and left ventricular ejection fraction between patients who died and those who stayed alive ( 2). There was no significant difference in these variables between the AMI patients with or without secondary cardiac events ( 2). The mean RR interval and mean standard deviation of the RR interval duration did not differ between unstable angina patients with or without secondary cardiac events. Mean standard deviation of the RR interval duration was significantly higher in the patients with unstable angina than in the patients with myocardial infarction, regardless of the presence of secondary cardiac events (s 2 and 3).

3 1: 2: 3: Clinical characteristics of 95 patients followed for 2 or more years after acute myocardial infarction (MI) or unstable angina. [view this table] Heart rate, heart rate variability, and left ventricular ejection fraction at hospital discharge of 71 patients followed-up 2 or more years after acute myocardial infarction with and without secondary event or cardiac death. [view this table] Heart rate and heart rate variability at hospital discharge of the 24 patients with previous unstable angina with (N=12) and without (N=12) further cardiac events after 2 or more years of the follow-up. [view this table] In an univariate logistic regression analysis, mean 24-hour RR interval, mean 24-hour standard deviation of RR intervals duration, and left ventricular ejection fraction at hospital discharge were significantly inversely associated with cardiac mortality (R=-0,19, p=0.02; R=-0.14, p=0.04; R=-0,23, p=0.01, respectively; Figs. 1 and 2). Figure 1: Standard deviations of individual RR intervals (heart rate variability) in patients without cardiac event (rhombs), with cardiac event (squares) or cardiac death (triangles). For statistical analysis, see 2. [view this figure] Figure 2: Standard deviations of individual RR intervals (heart rate variability) in patients without cardiac event (rhombs), with cardiac event (squares) or cardiac death (triangles). For statistical analysis, see 2. [view this figure] Discussion Increasing attention has been focused on risk stratification studies to identify patients at high risk after acute myocardial infarction (20-25). In the Framingham Study cardiovascular death increased progressively with increasing levels of heart rate (9). In the Paris Prospective Study, the heart rate also proved to be a significant predictor of subsequent cardiovascular death (12). Reduced heart rate variability in post myocardial infarction patients signals an increased risk of death (26,27). In the study of Kleiger and associates the relative risk of mortality after acute myocardial infarction was 5.3 times higher in the group with heart rate variability of less than 50 ms than in the group with a heart rate variability of more than 100 ms (18). Left ventricular ejection fraction is currently a widely used risk stratifier after myocardial infarction (28-30). Copie and associates found that the predischarge 24-hour mean heart rate, depressed heart rate variability, and lower left ventricular ejection fraction were strong predictors of mortality after myocardial infarction (31). To our knowledge, mean RR interval, standard deviation of RR intervals, and ejection fraction at hospital discharge have seldom been studied in postinfarction patients and patients with unstable angina pectoris. Our study suggests significant positive association between the heart rate and mortality in postinfarction patients. Heart rate variability and left ventricular ejection fraction were inversely associated with mortality in our postinfarction patients. Mean heart rate variability was below 100 ms in the nonsurvivors of myocardial infarction. A limitation of our study was that we did not assess the mode of death (arrhythmic versus nonarrhythmic). The relative risks of of time domain indexes seem to be independent of the type of death (cardiac or arrhythmic) taken as end point (32,33), suggesting that the prognostic power of the heart rate variability may be unaffected by the mode of death under scrutiny. Ejection fraction was not a significant determinant of any mode of the cardiac death in patients with depressed heart rate variability (21). It is not clear why long-term heart rate is such a strong predictor of mortality. Heart rate has a direct effect on the development of coronary atherosclerosis (34). Lower heart rate results in a longer diastolic total time when the coronary artery flow is more steady. Lower heart rate reduces the atherosclerosis because it prolongs periods of stable hemodynamic patterns. Heart rate also reflects the autonomic activity. Vagal stimulation and bradycardia increase the electrical stability of the myocardium (35). A shorter mean RR interval was shown to be a better predictor of sudden than nonsudden cardiac death (31). Compared with the mean heart rate, long-term heart rate variability is probably a more refined approach to the assessment of the same physiologic process and is consequently a slightly better risk stratifier after myocardial infarction (31). There was no relationship between secondary cardiac events and heart rate, heart rate variability and ejection fraction between postinfarction patients and patients with unstable angina pectoris. After myocardial infarction, heart rate and heart rate variability were considerably reduced, which had a strong prognostic power. After several weeks, these parameters recovered in uncomplicated infarctions and unstable angina.. However, reduced left ventricular ejection fraction, myocardial ischemia, and non-patency of the infarct-related coronary artery, hinder the recovery of heart rate and heart rate variability. Our earlier study showed that the heart rate and

4 heart rate variability were significantly lower in acute coronary heart disease patients on admission than on discharge from hospital (36). Patients with unstable angina pectoris had lower heart rate, higher heart rate variability, and higher left ventricular ejection fraction than those with myocardial infarction. This suggests better sympathovagal balance in patients with unstable angina than in postinfarction patients. Secondary cardiac events were more frequent in patients with unstable angina pectoris than in patients with myocardial infarction. This agrees with the physiopathology of unstable angina. Further studies are needed to demonstrate specific interventions in patients with high heart rate and low heart rate variability that would decrease mortality after myocardial infarction. References 1 Schroll M, Hagerup LM. Risk factors of myocardial infarction and death in men aged 50 at entry. A ten-year prospective study from the Glostrup populations studies. Dan Med Bull 1797;24: Medalie JH, Kahn RA, Neufelld HN, Risse E, Golbourdt U. Five year myocardial infarction incidence. II. Association of single variables to age and birthplace. J Chronic Disease 1973,26: Paul O, Lepper MH, Phelan WH. A longitudinal study of coronary heart disease. Circulation 1963;28: Morris JH, Gardner JM. Epidemiology of ischemic heart disease. Am J Med 1969;46: Malliani A. Association of heart rate variability components with physiological regulatory mechanisms. In: Malik M, Camm AJ, editors. Heart rate variability, 1st ed. Armonk: Futura; p Levy RL, White PD, Stroud WD, Hillman CC. Transient tachycardia: prognostic significance alone and in association with transient hypertension. JAMA 1945;129: Braunwald E, Sonnenblick EH, Ross J. Mechanisms of cardiac contraction and relaxation. In: Braunwald E, editor. Heart disease, 4th ed. Philadelphia: Saunders; p Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: The NHANES I epidemiological follow-up study. Am Heart J 1991;121: Kannel WB, Kannel C, Paffenbarger RS, Cupples LA. Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J 1987;113: Persky V, Stamler J, Paul O, Shekelle RB, Berkson MD, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiological studies. Am J Epidemiol 1980;112: Goldberg RJ, Larson M, Levy D. Factors associated with survival to 75 years of age in middleaged men and women. The Framingham study. Arch Intern Med 1996;156: Filipovsky J, Ducimetiere P, Safar ME. Prognostic significance of exercise blood pressure and heart rate in middle-aged men. Hypertension 1992;20: Kannel WB, Wilson P, Blair SN. Epidemiological assessment of the role of physical activity and fitness in development of cardiovascular disease. Am Heart J 1985;9: Pasternak RC, Braunwald E, Sobel BE. Acute myocardial infarction. In: Braunwald E, editor. Heart disease. 4th ed. Philadelphia: Saunders; p Braunwald E, Jones RH, Mark DB. Diagnosis and managing unstable angina. Circulation 1994;90: Feigenbaum H. Echocardiographic evaluation of cardiac chambers. In Feigennbaum H, editor. Echocardiography. 5th ed. Philadelphia: Lea & Febiger; p Malik M, Farrel T, Camm AJ. Circadian rhythm of heart rate variability after acute myocardial infarction and its influence on the prognostic value of heart rate variability. Am J Cardiol 1990;6: Kleiger RE, Miller JP, Bigger JT, Moss AJ, and the Multicentre Post-Infarction Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59: Rose G. Chest pain questionnaire. Milbank Mem Fund Quart 1964;43: Bosner MS, Kleiger RE. Heart rate variability and risk stratification after myocardial infarction. In: Malik M, Camm AJ, editors. Heart rate variability. 1st ed. Armonk: Futura; p Hartikainen JEK, Malik M, Staunton A, Poloniecki J, Camm J. Distinction between arrhythmic and non- arrhythmic death after acute myocardial infarction based on heart rate variability, signalaveraged electrocardiogram, ventricular arrhythmias and left ventricular ejection fraction. J Am Coll Cardiol 1996;28: Richards DAB, Byth K, Ross DL, Uther JB. What is the best predictor of spontaneous ventricular tachycardia and sudden death after myocardial infarction. Circulation 1991;83: Palatini P, Julius S. Heart rate and the cardiovascular risk. J Hypertens 1997;15:3-7.

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