Influence of MeforProlol on Heart Rate Variability in Skivors of Remote Myocardial Infarction Ellen C. Keeley, MD, Richard L. Page, MD, Richard A. Lange, MD, John E. Willard, MD, Charles Landau, MD, and 1. David Hillis, MD We assessed the influence of metoprolol on heart rate variability in surv’nrors of remote myocardial infarction. In 43 survivors of myocardial infarction 12 to 18 months previously (26 men and 17 women, aged 38 to 69 years), two 24-hour ambulatory electrocardiograms were recorded 2 weeks apart. In patients in group A (n = 28), who had taken metoprolol for the previous year, the drug was discontinued for 2 weeks, after which the first recording was done. The second recording was done 2 weeks after metoprolol was resumed. In patients in group 8 (n = IS), who had not taken metoprolol for the previous year, it continued to be withheld, and two 24-hour recordings were done 2 weeks apart. In group A, metoprolol increased the time domain variables in- dicative of enhanced vagal tone: root-mean-square suc- S everal large studies have shown that chronic p- blocker therapy substantially reduces mortality in survivors of myocardial infarction.lm5 Although the mechanism by which ,0 blockers accomplish this is not understood completely, it is hypothesized that their predominant effect is to reduce the incidence of ventricular fibrillation. Since diminished heart rate variability (HRV) appears to be a strong indepen- dent predictor of mortality in survivors of remote myocardial infarction, we performed this study to assess the influence of metoprolol on HRV in this patient population. METHODS Patient group: We studied 43 patients (26 men and 17 women, aged 38 to 69 years) who had survived a myocardial infarction 12 to 18 months previously. Pa- tients were excluded if they had congestive heart fail- ure, uncontrolled hypertension, atrial fibrillation, fre- quent atrial or ventricular ectopic activity, a permanent pacemaker, age >70 years, conduction system abnor- malities (i.e., right or left bundle branch block or in- traventricular conduction delay), significant valvular disease, autonomic neuropathy, treatment with antiar- rhythmic agents or medications with anticholinergic or sympathomirnetic activity, or a significant comorbid From the Department of Internal Medicine (Cardiovascular Division], University of Texas Southwestern Medical Center and Parkland Me- morial Hospital, Dallas, Texas. Manuscript received August 17, 1995; revised manuscript received October 25, 1995, and ac- cepted October 26. Address for reprints: 1. David Hillis, MD, Room CS 7.102, Uni- versity of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 7.5235-9047. cessive difference in normal RR (NN) intervals was 20 2 11 ms (mean 2 SD) without and 24 +- 9 ms with metoprolol (p < 0.051, and the proportion of NN that differ by >50 ms (pNNSO%) was 3.6 + 6.0 without and 5.5 k 6.0 with metoprolol (p < 0.05). In the frequency domain, the logarithms of the 26hour very low fre- quency and the 24-hour high-frequency power (reflect- ing parasympathetic activity) were increased (5.12 + 1.03 and 4.48 + 1.5 1, respectively, without metoprolol; 5.32 2 0.99 and 4.83 ? 1.24, respectively, with me- toprolol, p < 0.05 for both). Thus, in survivors of remote myocardial infarction, metoprolol enhances parasym- pathetic cardiac activity in the time and frequency do- main measures of heart rate variability. (Am J Cardiol 1996;77z557-560) condition (i.e., severe pulmonary disease, azotemia, or uncontrolled diabetes mellitus) . Experimental protocol: Each patient provided written informed consent to participate in the study, which was approved by the institutional review board of the Uni- versity of Texas Southwestern Medical Center. Group A (n = 28): At the time that informed consent was obtained in these patients, each had been taking metoprolol, 25 to 200 mg/day, for ~-12 months. On entering the study, each discontinued metoprolol in- gestion over 4 to 6 days, after which he or she received no metoprolol for 2 weeks. At the end of this 2-week ‘ ‘no metoprolol” period, a 24-hour ambulatory elec- trocardiographic recording was obtained. Subse- quently, each patient resumed metoprolol consumption (at the same dose as previously). Two weeks later, another 24-hour\ ambulatory electrocardiographic re- cording was obtained. During the entire testing period, each patient’s other medications were not altered. Thus, in the 28 group A patients, a 24-hour ambulatory electrocardiographic recording was performed after 2 weeks of no-metoprolol therapy and after 2 weeks of metoprolol therapy. Group B (n = 15, controls): At the time that in- formed consent was obtained in these patients, none had taken metoprolol for 212 months. In each of these patients, metoprolol continued to be withheld while two 24-hour ambulatory electrocardiographic recordings were obtained 2 weeks apart. Variables assessed: The digitally sampled electro- cardiographic data were transferred from the Delmar Avionics scanner (Holter Analysis System model 563, Irvine, California) to a computer (StrataScan, software version F, Delmar, Irvine, California) for analysis of HRV, which was measured in accordance with previ- CORONARY ARTERY DISEASE/METOPROLOL AND HEART RATE VARIABILITY 557