The Association Between Residual Myocardial Ischemia and Heart Rate Variability Early After Acute Myocardial Infarction

The Association Between Residual Myocardial Ischemia and Heart Rate Variability Early After Acute Myocardial Infarction

Miguel Quintana, M.D., Ph.D.,* Kaj Lindvall M.D., Ph.D.,T and Niklas Storck M.D.$ From the Karolinska lnstitute at the "Section of Cardiology, Danderyd Hospital; the ?Heart, Vessels and Lung Center, Huddinge Hospital; and the #Department of Clinical Physiology South Hospital, Stockholm, Sweden

Background: Residual myocardial ischemia and decreased heart rate variability (HRV) are common findings during the acute phase of acute myocardial infarction. Both signs have been associated with a poor prognosis. The present study investigated the association between residual myocardial ischemia and HRV in the early phase after AMI.

Patients and Methods: Seventy-four patients were monitored with ambulatory electrocardiography during 23 5 1 hours, 4 ? 1 days after AMI. In addition, 24 healthy individuals (controls) with similar age and gender were also monitored. HRV was computed in time and frequency domains. Residual myocardial ischemia was defined as the presence of ST-segment depression during ambulatory electrocardiography, defined as a 2 0.1 mV horizontal or downsloping ST-segment deviation from the reference level, elapsing 1 minute or longer, measured 80 ms after the J point.

Results: Residual myocardial ischemia was found in 22 (30%) patients. Some time-domain and all frequency-domain measures of HRV were lower in patients showing residual myocardial ischemia compared with those without residual myocardial ischemia. All time- and frequency-domain measures of HRV were higher in controls compared with patients with residual myocardial ischemia. Only SDNN and low frequency band values were lower in patients without residual myocardial ischemia compared with healthy controls. Both residual myocardial ischemia and a decreased HRV were associated with poor in-hospital outcome.

Conclusions: Patients showing residual myocardial ischemia during ambulatory electrocardiography performed early after AM1 had lower values of HRV compared with those without residual myocardial ischemia. The causality between these findings are not still defined and deserve further

heart rate variability; myocardial ischemia; ST-segment depression; acute myocardial infarction

research. A.N.E. 1998;3(4):288-297

Heart rate variability (HRV), a measure of the cardiac sympathovagal balance,'-3 has emerged as a marker of poor prognosis in patients recovering from an acute myocardial infarction (AMI).4-9 Al- though certain clinical variables, among them, age, the presence of diabetes mellitus, previous myocardial infarction, and the presence of heart failure, are associated with a decreased HRVI1O-lZ the factors determining the time- and frequency-domain

values of HRV early after AM1 are still poorly un- derstood. lo Although some objective measurements of left ventricular function and infarct size have shown some degree of correlation with measures of HRV,5,9c10r13~14 the role of myocardial ischemia occurring early after infarction on HRV has not been studied. It is known from experiments in animal models that the reduction of HRV induced by myocardial ischemia may play an important role

This study was supported by grants from the Swedish Heart Lung Foundation and the Karolinska Institute. Address for reprints: Miguel Quintana, M.D., Ph.D. Division of Cardiology, Department o f Internal Medicine, Danderyd Hospital. S 182 88 Danderyd. Stockholm, Sweden. Fax: 46-8-622 68 10. E-mail: [email protected]

288

A.N.E. October 1998 Vol. 3, No. 4 Quintana, et al. MI and Heart Rate Variability 289

in the maintenance of electrical ~tability. '~ It is also known that ventricular fibrillation and sudden death induced by myocardial ischemia occurs more frequently in the presence of a decreased baroreflex ~ensi t ivi ty . '~ ,~~ Although HRV is a potential tool for risk stratification after AMI, the exact mechanism by which a decreased HRV implies a poor prognosis, and the possible role that myocardial ischemia could play, have not been investigated. The present investigation studied ambulatory electrocardiography in patients recovering from an AM1 and evalu- ated the possible association between residual myocardial ischemia and HRV.

PATIENTS AND METHODS Study Population

Ambulatory electrocardiography was performed in 74 consecutive patients 4 2 2 days after hospital admission for AMI. Exclusion criteria were age > 75 years, atrial fibrillation, second- or higher degree atrioventricular (AV) block, left bundle branch block or QRS complex > 120 ms, cardiogenic shock, cancer or other unrelated diseases, and un- willingness to participate. Myocardial infarction was diagnosed clinically and confirmed by electrocardiographic changes or by an increase in creatine kinase to > 2 times normal with an associated increase in creatine kinase MB (CK-MB] isoenzyme to > 5% of total creatine kinase. The mean age of the studied population was 61 ? 9 years (standard deviation [SD]) with a mean CK-MB value of 1.48 ? 1.05 yKat/L. Sixty patients (81%) were males, 26 (35%) had an anterior infarction, 50 (68%) had a Q wave infarction, 28 (38%) had a history of systemic hypertension, 15 (20%) had had a previous myocardial infarction, 8 (11%) had diabetes mellitus, and 40 (54%) were present smokers. During hospitalization, 22 patients (30%) developed heart failure and 11 (15%) had angina pectoris after the index infarction.

Control Group A group of 24 individuals with similar mean age

and gender was recruited to ensure the reliability of the algorithm used for the ST-segment analysis and for the two-stage analysis of time and frequency domain of RR intervals. These individuals were used as f'controls"' They were recruited from the waiting list at the Department of General Sur- gery. None had a history of previous angina pecto-

ris or myocardial infarction. A normal rest ECG, a normal echocardiogram, and a normal maximal exercise test were necessary in order for the individual to be included as a control subject. Approval of the local ethics committee was obtained. All patients received written information and gave in- formed consent.

Ambulatory Electrocardiographic Monitoring

The patients and controls were monitored during a mean period of 23 t 2 hours. Frequency-modu- lated, reel-to-reel two-channel MEDILOG 4000- I I P ambulatory ECG recorders (Oxford Medical Limited, Oxford, UK) were used. Approximately 20 seconds of ECG calibration and two-channel ECG signals were recorded with the patients in different body positions (lying on back and on left side, sitting, standing, after hyperventilation, and during arm movements) to document posture-induced ST- segment changes. Five electrode positions were used to record two bipolar CV1 and CV5 ECG leads. All patients were restricted to limited levels of activity, including sitting in bed or walking at the ward during ambulatory electrocardiographic monitoring.

Detection of Residual Myocardial Ischemia

Twenty-four - hour tapes were played back at 60X real-time by special-purpose hardware (Replay 11", Reynolds Medical, Hertford, UK) in a custom- designed computer analysis program (Daltek", Bor- lange, Sweden). The isoelectric reference level (PR level) was determined as the average voltage in a short time interval before the onset of the QRS complex. ST-segment depression was defined as a downsloping or horizontal deviation from the reference level by ? 0.1 mV, lasting 2 1 minute as measured 80 ms after the J point. Individual episodes of ST-segment deviation were separated by at least 2 minutes. During each episode with ST- segment depression z 0.1 mV, computer-generated ECG strips were printed out to determine the accuracy of computer reports. When the visual analysis of ECG strips did not correspond with computer- averaged reports, the operator manually edited the QRS complex with new reference points, and the computer performed the measurements again. Pa- tients with prolonged or fixed ST depressions were considered to be without ST depression^.'^^'^

290 A.N.E. October 1998 Vol. 3, No. 4 Quintana, et al. MI and Heart Rate Variability

Analysis of HRV The electrocardiographic recordings were digi-

tized and QRS labeled by use of the Daltek system. The RR intervals, including the labeling of the QRS complexes, were then exported to a text file that was further analyzed on a personal computer with use of our own software. Further analysis was done in units of 500 RR intervals. Gaps in the RR series resulting from ectopic beats or noise were filled with linear splines according to the method described by Albrecht and Cohen." To be accepted for further analysis, it was necessary for an interval to have at least 96% of the QRS complexes classified as normal by the Daltek system.'l

After editing, the following time-domain measures were obtained from the time series of normal RR intervals: mean of normal RR intervals (mean NN), variance, SD of all normal RR intervals in the entire 24-hour ECG recording (SDNN), SD of the average normal RR intervals for all 500 RR groups of a 24-hour ECG recording (SDANNi), and root mean square successive difference (r-MSSD). The RR series were transformed to the frequency domain by the moving average procedure described by Kay and Marple." Frequency-domain measures of RR variability were computed by integration of their frequency intervals in three frequency bands as described by Bigger and FleissZ3: very low frequency ([VLF] = 0.003- < 0.04 Hz), low frequency ([LF] = 0.04- < 0.15 Hz), and high frequency ([HF] = 0.15- 0.4 Hz). In addition, the total power spectrum (TPS) was calculated in the 0.0033-0.4 Hz area.

Exercise Stress Testing Seventy patients performed a symptom-limited

bicycle ergometer exercise stress test 7 t 4 days after admission. Twelve-lead ECGs were recorded before exercise, at intervals of 1 minute during exercise, at peak exercise, immediately after recovery, and 2, 4, 6, and 10 minutes after exercise. Systolic blood pressure was recorded before exercise, every second minute during exercise, at peak exercise, and after postexercise recovery. Addi- tional details concerning exercise test have been described p r e v i o ~ s l y . ~ ~ Tests were considered posi- tive for ischemia if z 1 mm of horizontal or downsloping ST-segment depression, measured 80 ms after the J point, appeared in at least two consecutive leads, compared with the baseline ECG. Exer- cise ECGs were blindly interpreted by two investigators. In case of disagreement, a third interpreta-

tion was done by an independent investigator, and the majority opinion prevailed.

Statistical Analysis The power spectral measures of HRV were trans-

formed into natural logarithms (Ln) since their dis- tributions were positively skewed. The data are presented as the mean 2 SD of the Ln-transformed data. Statistical significance was tested by use of the t-test for continuous and normal distributed variables. Categorical variables were tested with Yates corrected Chi-square test. Comparisons among groups were done with analysis of variance (Turkey test for unequal sample sizes). A P value of < 0.05 was considered of statistical significance.

RESULTS Residual Myocardial Ischemia

A total of 2276 hours were recorded in 74 patients and 24 controls. A group of 22 patients (30%) showed residual myocardial ischemia, defined as the presence of at least one episode of ST-segment depression. These patients had a total of 340 episodes (mean 14 2 10 episodes per patient) with a median duration of 341 -C 380 minutes (range 6- 1088 min). The mean ST-segment depression value was 0.3 2 0.18 mV (range 0.11-0.64 mV).

One individual (4%) in the control group showed ST-segment depression. Seven patients (9.4%) showed prolonged or "fixed" ST-segment depression and were consequently considered as without residual myocardial ischemia. All other characteristics of the patients with and without residual myocardial ischemia are presented in Table 1.

In-Hospital Mortality During the in-hospital period, 5 (23%) patients

with residual myocardial ischemia died versus 1 (2%) without residual myocardial ischemia (P < 0.01). Among measures of HRV, Ln VLF was lower in patients who died during hospitalization than in patients discharged (5.4 ? 1.1 vs 6.4 ? 0.8, P < 0.05). All other measures were similar in both groups.

Clinical Characteristics, Pharmacological Therapy, and HRV

Regarding pharmacological treatment, patients on aspirin had higher values of frequency-domain variables (TPS, VLF, LF) than those not receiving

A.N.E. October 1998 0 Vol. 3, No. 4 Quintana, et al. MI and Heart Rate Variability 9 291

Table 1 . Clinical Characteristics of Patients with and without Residual Myocardial Ischemia

RM I No RMI Characteristics n = 22 n = 52 P

Age (years +- SD) 60 +- 9 61 + 9 NS CK-MB (pKat/L +- SD) 1.38 +- 0.9 1.58 2 1.2 NS Males 18 (821 42 (811 NS Females 4 (18) 10 (191 NS Anterior infarction 7 (32) 19 (42) NS Inferior infarction 10 (45) 23 (51) NS Undetermined localization 5 (231 4 (8) NS Q wave infarction 17 (77) 33 (63) NS Non Q wave infarction 5 (23) 19 (37) NS Hypertension 10 (45) 18 (35) NS Previous infarction 7 (321 8 (15) NS Diabetes mellitus 2 (91 6 (121 NS Present smokers 16 (72) 24 (46) 0.04 Angina pectoris* 6 (27) 5 (10) NS Heart failure* 9 (41) 13 (25) NS Mean RR (ms L SD) 806 2 179 869 % 184 NS In-hospital mortality 5 (23) 1 (2) < 0.01

All numbers are expressed as absolute values with percentages in parenthesis if not explained otherwise. * = Assessed during the hospitalization period; CK-MB = MB fraction of the creatinine kinase enzyme: RMI = residual myocardial ischemia defined as the presence of ST-segment depression during ambulatory ECG monitoring; P = Yates corrected chi2 or two-tailed t-test.

aspirin. Patients treated with heparin also showed higher values than those not treated with this drug (SDANNi, TPS, VLF, LF, HF). Patients on diuretics showed higher LF values. Treatment with thrombolytics, beta-blockers, calcium antagonists, di- goxin, nitrates, angiotensin converting enzyme in- hibitors did not influence the values of HRV (Tables 2a and 2b). Among clinical characteristics, patients with non-Q wave infarction, previous myocardial infarction, diabetes mellitus, and those presenting heart failure during hospitalization showed lower variance and lower frequency-domain values of HRV (Tables 3a and 3b).

Residual Myocardial Ischemia and HRV Table 4 shows the time- and frequency-domain

values of HRV in controls and according to the presence or absence of residual myocardial ischemia. Comparisons were done among the three groups. As depicted, all frequency-domain measures of HRV were higher in patients with residual myocardial ischemia compared with those without residual myocardial ischemia. This difference was more pronounced when comparing controls and patients with residual myocardial ischemia. The

same was true for some values of time domain (SDNN, SDANNi, and r-MSSD). Controls and patients without residual myocardial ischemia did not differ considerably, apart from SDNN and Ln LF measures.

Among 20 patients with residual myocardial ischemia on ambulatory electrocardiography, 16 (80%) had myocardial ischemia during exercise test performed before discharge (Kendall coefficient of concordance K = 0.4, P < 0.0001). Two of the 22 patients with residual myocardial ischemia on ambulatory electrocardiography died before exercise test.

Association Between Ischemia During Exercise Test and HRV

Table 5 shows measures of HRV in frequency and time domains according to the presence of myocardial ischemia during exercise test, defined as the presence of ST-segment depression in at least two consecutive leads. No differences between groups were found.

DISCUSSION The results of the present study indicate that pa-

tients with residual myocardial ischemia early after


Table 2a. Pharmacological Therapy and Measures of HRV in Frequency Domain (Table 2a) Expressed as Natural Logarithms (Ln t 1 SD) and in Time Domain (t 1 SD) (Table 2b)

Pharmacological TPS VLF LF HF Treatment (Lnl (Ln) (Ln) (Lnl

Aspirin Y = 66 N = 8

Beta-blockers Y = 46 N = 28

Calcium antagonists Y = 18 N = 56

N = 39 Heparin Y = 46

N = 28 Nitrates Y = 2 3

N = 51 Diuretics Y = 34

N = 40

Thrombolytics Y = 35

7.1 t 0.9* 6.3 t 1.2 7.1 t 1.0 6.9 t 1.0 6.8 t 1.0 7.0 2 0.9 7.0 2 0.8 7.0 c 1 . 1 7.2 t 0.9* 6.6 i 0.9 6.8 i 1.0 7.1 t 1.0 6.8 2 1 . 1 7.1 i 0.9

6.5 t 0.8* 5.4 t 0.7 6.5 ? 0.9 6.2 2 0.8 6.2 2 0.9 6.4 t 0.8 6.4 t 0.7 6.3 t 1.0 6.5 t 0.8* 6.0 2 0.9 6.2 2 0.9 6.4 t 0.8 6.2 2 0.9 6.5 t 0.8

5.7 t 1.0t 4.7 t 1.2 5.6 t 1 . 1 5.4 t 1 . 1 5.3 t 1 . 1 5.7 2 1 . 1 5.6 t 0.9 5.5 t 1.3 5.7 i 1 . 1 5.0 t 1 . 1 5.3 2 1 . 1 5.7 t 1 . 1 5.2 c 1.2* 5.8 2 1.0

5.0 2 1.2 4.8 t 1.8 5.0 t 1.2 4.9 i 1.3 4.9 2 1.4 5.0 2 1.2 4.9 i 1 . 1 5.0 t 1.4 5.2 t 1.4t 4.5 i 0.8 4.8 ? 1.3 5.0 t 1.2 5.0 c 1.5 4.9 2 1.0

~~

Two-tailed t-test. * < 0.05; t < 0.01. HF = high frequency; LF = low frequency; Ln = natural logarithms; SD = standard deviation; TPS = total power spectrum; VLF = very low frequency.

Table 2b.

Pharmacological Treatment

Aspirin

Beta-blockers

Calcium antagonists

Throm bolytics

Heparin

Nitrates

Diuretics

Y = 66 N = 8 Y = 46 N = 28 Y = 1 8 N = 56 Y = 3 5 N = 39 Y = 46 N = 28 Y = 2 3 N = 51 Y = 34 N = 40

2487 t 2085 2024 t 2697 2791 i 2448 1865 2 1410 2468 t 2008 2426 t 221 6 2157 t 1745 2691 2 2462 2758 2 2225* 1970 t 1960 2201 2 1844 2521 ?2281 2541 c 2068 2307 -t 2231

103 t 41 92 2 23

103 5 36 99 t 45 98 * 33

103 t 42 95 t 36

108 5 42 109 2 40* 91 2 3 5

103 .-t 43 101 5 3 8 105 t 34 98 2 25

48 t 30 33 -+ 22 49 t 27 42 t 32 41 ? 18 48 t 32 45 2 30 48 t 29 52 i 33* 37 2 18 43 t 24 48 2 32 47 t 42 46 2 37

44 i 50 45 2 44 42 2 47 48 t 54 36 5 25 47 ? 55 36 i 45 51 t 53 53 ? 58* 30 t 24 42 -t 55 45 i 47 54 63 35 t 31

~~

Two-tailed t-test. * < 0.05. r-MSSD = root mean square successive difference; SDANNi = standard deviation of average normal RR intervals: SDNN = standard deviation of all normal RR intervals.

AM1 had lower time- and frequency domain values of HRV compared with patients without residual myocardial ischemia. Differences between controls and patients with residual myocardial ischemia were found at even higher levels of significance. When the control group was compared with the group without residual myocardial ischemia, only SDNN and Ln LF were found to be lower in the group without residual myocardial ischemia than in controls.

Although HRV has been studied during the acute

and the convalescent phases of AM1 in several stud- iesI5-’ few of those have investigated the causes or determinants of HRV. Certain clinical characteristics have been associated with a decreased HRV in the general population, as well as in populations of patients with coronary artery disease and in postin- farction cohorts. For example, diabetes mellitus, previous myocardial infarction, and some indices of heart failure, together with some laboratory data indicating the infarction size (maximal enzyme level, left ventricular ejection fraction, wall motion

A.N.E. October 1998 Vol. 3 , No. 4 Quintana, et al. MI and Heart Rate Variability 293

Table 3a. Clinical Characteristics and Measures of HRV in Frequency Domain (Table 3a) Expressed as Natural Logarithms (Ln t 1 SD) and in Time Domain (I 1 SD), Table 3b

~

Clinical Characteristics ~~

Males

Anterior

Q wave

Previous infarction

Hypertension

Diabetes mellitus

Heart failure

Angina pectoris

Y = 60 N = 14 Y = 26 N = 48 Y = 50 N = 24 Y = 15 N = 59 Y = 28 N = 46 Y = 8 N = 66 Y = 2 2 N = 52 Y = 1 1 N = 63

7.0 2 1.0 7.0 I 1.0 6.9 I 1.1 7.2 t 0.8 7.2 t 0.9 6.6 t 1.0* 6.6 t 1.1

6.9 I 0.9 7.1 t 1.0 6.3 t 1.4 7.1 I 0.9 6.7 t 1.2 7.1 t 0.8 6.7 2 0.8 7.0 t 1.0

7.1 2 0.9

6.4 t 0.9 6.2 t 0.7 6.3 t 1 .O 6.5 t 0.7 6.5 t 0.8 6.0 t 0.9* 5.9 I 0.9* 6.4 t 0.8 6.2 t 0.8 6.4 2 0.9 5.5 I 1.3* 6.4 t 0.8 6.0 2 1 .O* 6.5 t 0.8 6.0 2 0.8 6.4 t 0.9

5.6 It 1.1 5.4 t 1.1 5.5 t 1.2 5.8 t 0.9 5.7 t 1.0 5.1 t 1.1* 4.9 2 1.2* 5.7 2 1.0 5.4 2 1 .o 5.7 +- 1.2 4.8 t 1.5 5.6 t 1.0 5.1 t 1.3* 5.7 t 1.0 5.3 t 1.0 5.6 ~t 1.1

4.8 t 1.1 5.3 ? 1.6 4.9 t 1.2 5.1 t 1.3 5.1 ? 1.3 4.6 t 1.1 4.7 2 1.4 5.0 t 1.2 4.8 2 1.3 5.0 ~f: 1.2 4.7 t 1.6 5.0 t 1.2 4.8 2 1.7 5.0 t 1.1 4.8 2 1.1 5.0 2 1.3

Two-tailed t-test. * < 0.05. HF = high frequency; LF = low frequency; Ln = natural logarithm; SD = standard deviation; TPS = total power spectrum; VLF = very low frequency.

Table 3b.

Clinical Variance SDNN SDANNi r-MSSD Characteristics (ms2) (ms) (msl (ms)

~~ ~~

Males Y = 60 2249 2 2007 100 t 39 45 5 30 40 t 43 N = 14 31 13 I 2556 107 5 40 50 t 27 58 t 67

Anterior Y = 26 2563 t 2506 108 t 43 46 t 30 41 ? 3 6 N = 48 2557 t 1966 102 t 39 49 I 31 50 t 60

N = 24 2077 t 2057 98 t 43 38 t 32 38 2 55 Previous infarction Y = 15 1301 t 1237* 103 2 52 37 t 26 55 ? 69

N = 59 2692 I 2231 101 2 3 6 48 t 30 41 5 4 4 Hypertension Y = 28 2455 t 1980 100 2 37 44 t 22 48 ? 55

42 ? 46 N = 46 2420 2 2266 103 2 41 47 t 33 Diabetes mellitus Y = 8 2022 t 2766 101 2 4 9 35 t 25 49 t 48

N = 66 2480 t 2089 102 5 39 47 t 29 43 t 50 Heart failure Y = 22 1598 I 1330* 1041t 51 45 5 40 60 t 75

N = 52 2768 t 2323 100 t 34 47 I 23 37 2 32 Angina pectoris Y = 1 1 19132 1690 a9 t 26 37 t 18 36 & 28

N = 63 2531 12219 104 2 41 48 t 31 45 5 52

Q wave Y = 50 2 6 0 9 t 2141 103 t 32 501 19 47 5 36

Two-tailed t-test. * < 0.05. r-MSSD = root mean square successive difference; SDANNi = standard deviation of average normal RR intervals; SDNN = standard deviation of all normal RR intervals.

score), have been associated with a decreased HRV.5,gf1O- 14 However, the importance of residual myocardial ischemia as a determinant of HRV in

values in patients with or without ST-segment shifts. Myocardial ischemia was, however, poorly defined in the last study.

those patients has been analyzed only in few studies, with controversial r e s ~ l t s . ~ ~ * ~ ~ While Bigger et a1.26 found that LF and HF components decreased

Relationship Between Residual Myocardial Ischemia and HRV

during ST-segment depression, Singh et aLZ5 did not find any difference in time- and frequency-domain

Recent studies have shown that patients with coronary artery disease have lower values of HRV


Table 4. Measures of Heart Rate Variability in Frequency and Time Domains in Patients with and without Residual Myocardial Ischemia and in Controls

A B C Controls No RMI RMI A v s . B Bvs .C Avs. C

Variables n = 24 n = 22 n = 52 2P 2P 2P

Time domain

Mean NN 826 2 103 8695 191 806 ? 179 NS NS NS SDNN 161 ? 56 108 2 42 87 5 31 0.007 0.02 < 0.0001 SDANNi 5 4 2 17 54 2 34 3 7 ? 16 NS 0.007 0.0001 rMSSD 72 5 61 49 5 58 31 5 2 6 NS NS 0.0002

Frequency domain

Ln TPS 7.6 5 0.5 7.3 2 1.0 6.6 ? 0.8 NS 0.0 1 0.000 1 Ln VLF 6.9 t 0.5 6.6 5 0.8 6.1 2 0.7 NS 0.02 0.000 1 Ln LF 6.4 2 0.7 5.9 5 1.1 5.2 ? 1.0 0.02 0.0 1 < 0.0001 Ln HF 5.3 ? 0.8 5.2 5 1.3 4.5 ? 1.0 NS 0.01 0.004

Comparisons among groups using ANOVA. HF = high frequency; LF = low frequency; Ln = natural logarithm; NN = normal RR interval; r-MSSD = root mean square successive difference; SDANNi = standard deviation of average normal RR intervals; SDNN = standard deviation of all normal RR intervals; TPS = total power spectrum; VLF = very low frequency.

when compared with the general In addition, other authors2* have demonstrated a statistical association between the severity of coronary artery disease, assessed by coronary angiogra- phy, and the measures of HRV. However, the effects of myocardial ischemia on HRV have been analyzed only in a few studies in patients with coro-

nary artery di~ease.”-~l Pozzati et al.” found that during ambulatory monitoring in patients with stable and unstable angina, the values of SDNN and pNN50 were lower during the 5 minutes preceding ST-segment changes indicative of myocardial ischemia than during the hour preceding ST-segment changes. Furthermore, they found that a decrease

Table 5 . Measures of Heart Rate Variability in Frequency and Time Domains in Patients with and without Residual Myocardial Ischemia During Exercise Test, Defined as the Presence

of ST-Segment Depression in at Least Two Consecutive Leads

Exercise Test

ST-Segment Depression No ST-Segment Depression Variables n = 34 n = 36 P

Time domain

Mean NN SDNN SDANNi rMSSD Variance

868 5 195 104 5 44 47 2 3 48 5 64

2215 2 1700

840 -t 181 100 -+ 37 45 -t 28 41 5 32

2670 2 2563

Frequency domain

Ln TPS Ln VLF Ln LF Ln HF

6.9 2 1.0 6.3 2 0.8 5.5 2 1 .1 4.8 2 1.4

7.1 2 0.9

5.6 2 1.2 5.0 -c 1.2

6.4 % 0.8

NS NS NS NS NS

NS NS NS NS

P = two-tailed t-test. HF = high frequency; LF = low frequency; Ln = natural logarithm; NN = normal RR interval; r-MSSD = root mean square successive difference; SDANNi = standard deviation of average normal RR intervals; SDNN = standard deviation of all normal RR intervals; TPS = total power spectrum; VLF = very low frequency.


of SDNN preceded 95% of all ischemic episodes. Goseki et al.,30 studying HRV by means of ambulatory ECG monitoring in patients with stable angina, found that HRV was lower during ischemic episodes, regardless of treatment with beta-blockers. However, those studies did not assess HRV during and after the ischemic periods and, therefore, the direct effects of ischemia on HRV were not completely studied. Vardas et al.,31 studying patients with extensive coronary artery disease, found a steep linear reduction in the HF component before nocturnal episodes of myocardial ischemia, a grad- ual increase during the episode, and a trend to nor- malization 6 minutes after the end of the episode. The LF component showed a more complex and erratic pattern.

HRV, Residual Myocardial Ischemia, and Prognosis

In the present study, patients with residual myocardial ischemia and a decreased HRV had a poor in-hospital outcome. As previously stated, a decreased HRV and the presence of residual myocardial ischemia detected by ambulatory electrocardiography have been implied as important markers of poor prognosis in post-AM1 patients as well as in patients with unstable angina pectoris.4-10~14~18~1’ We and other have also shown that residual myocardial ischemia detected by ambulatory monitoring is an important risk marker, independent of other clinical variables, during long- term follow-up.

The mechanisms by which a decreased HRV leads to a poor prognosis are still unknown and deserve further investigation. The most common causes of death in survivors of myocardial infarction are sudden death (purely arrhythmic or ischemic) , reinfarction (followed by cardiogenic shock or arrhythmic death) , and progressive heart failure (with or without arrhythmic death). Al- though it is well accepted that patients with conges- tive heart failure had decreased values of HRV, it is less known if this decreased HRV is a consequence of left ventricular dysfunction or if it is an early marker for patients who will develop left ventricular dysfunction and heart failure later on. The mode of death in patients with or without progressive heart failure after myocardial infarction is explained in some cases by a lethal arrhythmia as a late event.33 These lethal arrhythmias might or might not be preceded by an ischemic event.34

When an ischemic event precedes a lethal arrhythmia, a decreased HRV has been found to be present even some time before the onset of the ischemic episode.” In cases of arrhythmic sudden death without a preceding ischemic event, HRV has been found to be decreased some time before the occurrence of the lethal a r r h ~ t h m i a ~ ~ ; however, these findings are contr~versial .~~

Myocardial Ischemia at Rest, During Exercise, and HRV

Although the presence of residual myocardial ischemia during ambulatory electrocardiography was strongly associated with poor values of HRV, myocardial ischemia detected during exercise test did not show any statistical correlation with measures of HRV. The Kendall coefficient of concordance between residual myocardial ischemia detected by ambulatory electrocardiography and exercise test was, however, relatively good. The apparent lack of concordance between measures of HRV and residual myocardial ischemia detected by two different methods may be explained by some factors: the mechanisms behind residual myocardial ischemia during ambulatory electrocardiography and exercise test are different,37 and HRV re- covers during time after AM1 (ambulatory electrocardiography and exercise test were actually performed several days apart).23

Interestingly, patients treated with aspirin and heparin showed higher values of HRV than those not treated with these drugs. It is well known that both drugs reduce ischemic events in patients with acute coronary ~yndrornes .~~*~’ It could be postu- lated that ischemia induced by unstable plaques had a stronger correlation with HRV than exercise- induced ischemia. However, it must be emphasized that the patients were not randomly allocated to different treatments and that the statistical associa- tions may be spurious.

Although the cause-effect relationship between myocardial ischemia and decreased HRV has not yet been completely elucidated, it seems probable that this is the case. This has been demonstrated in many postinfarct studies5-’’ and in patients with unstable angina. l4 In the last group of patients, transient myocardial ischemia, rather than myocardial necrosis, is the most common finding. How- ever, Yoshio et a1.,@ studying patients with variant angina, found that HRV was increased before ischemic episodes during ambulatory electrocardiogra-

296 A.N.E. . October 1998 Vol. 3, No. 4 Quintana, et al. MI and Heart Rate Variability

phy. The authors concluded that an increased HRV was the consequence of an increased sympathovagal tone leading to vasoconstriction and myocardial ischemia. These findings were, however, also found in the absence of ST-segment elevation and in control subjects and, therefore, were not specific for coronary spasm and variant angina.

Study Limitations

The statistical association between residual myocardial ischemia and HRV was strong. Neverthe- less, the causal relationship between these factors was not analyzed in the present study. The ambulatory electrocardiography recordings for assessment of residual myocardial ischemia and HRV were analyzed by different algorithms and softwares. The timing of the ischemic events with measures of HRV should be analyzed in an integrated manner to study HRV before, during, and after ischemic periods as well as in nonischemic periods.

Possible Clinical Applications

The evidence that a decreased HRV depends on the effects of residual myocardial ischemia is elu- sive. What seems to be more important is to see if the combination of the factors could improve the risk stratification of patients with coronary artery disease. Although myocardial ischemia and a decreased HRV are important risk markers, it is obvi- ous that not all patients with residual myocardial ischemia and decreased HRV had a poor prognosis. We have recently shown41 that residual myocardial ischemia and HRV confer independent prognostic value in post-AM1 patients. This observation must be confirmed in a wider population of patients with AM1 or acute coronary syndromes.

Currently, on-line ECG monitoring of patients with acute coronary syndromes is clinically feasi- ble by means of on-line vectorcardiography and on-line 12-lead ECG monitoring. Detection of myocardial ischemia, myocardial reperfusion after thrombolytic therapy, and assessment of prognosis in patients with acute coronary syndromes have been possible with these It would be desirable to implement algorithms used to measure HRV into these diagnostic tools, in order to increase the information that can be obtained. This increased information will probably lead to better clinical management. Future studies in this direc- tion are warranted.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

REFERENCES Bigger TJ, Fleiss JL, Steinman RC, et al. RR Variability in healthy, middle-aged persons compared with patients with chronic coronary heart disease or recent acute myocardial infarction. Circulation 1995; 1936- 1943. Hayano J, Skakibara Y, Yamada A, et al. Accuracy of assessment of cardiac vagal tone by HRV in normal subjects. Am J Cardiol 1991;67:199-204. Lombardi F, Sandrone G, Pernpruner S, et al. Heart rate variability as an index of sympatho-vagal interaction after acute myocardial infarction. Am J Cardiol 1987;601239- 1245. Quintana M, Storck N, Lindblad LE, et al. Heart rate variability as a means of assessing prognosis after acute myocardial infarction: A three-year follow-up study. Eur Heart J

Kleiger R, Miller P, Bigger T, et al., and the Multicenter Post-Infarction Research Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59:256- 262. Cripps TR, Malik M, Farrell TG, et al. Prognostic value of reduced heart rate variability after myocardial infarction: Clinical evaluation of a new analysis method. Br Heart J

Bigger T, Fleiss Jt Steinman R, et al. Frequency-domain measures of heart period variability and mortality after myocardial infarction. Circulation 1992; 85:164- 171. Bigger T, Fleiss J, Rolnitzky L, et al. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol 1993;21:729-736. Vaishnav S, Stevenson R, Marchant B, et al. Relation between heart rate variability early after acute myocardial infarction and long-term mortality. Am J Cardiol 1994; 73:

Valkama JO, Huikuri HV, Airaksinen KEJ, et al. Determi- nants of frequency domain measures of heart rate variability in the acute and convalescent phases of myocardial infarction. Cardiovasc Res 1994; 28: 1273- 1276. Tsuji H, Venditti FJ, Manders ES, et al. Determinants of heart rate variability. J Am Coll Cardiol 1996;28:1539- 1546. Malpas SC, Mailing TJ. Heart rate variability and cardiac autonomic function in diabetes. Diabetes 1990; 39:1177- 1181. Dambrink JHE, Tuininga YS, van Gilst WH, et al., for the CATS Investigators. Association between reduced heart rate variability and left ventricular dilatation in patients with a first anterior myocardial infarction. Br Heart J 1994; 72514- 520. Casolo GC, Stroder P, Signorini C, et al. Heart rate variability during the acute phase of myocardial infarction. Circula- tion 1992; 85:2073 -2079. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989;69: 1049- 1069. Schwartz PJ, Vanoli E. Cardiac arrhythmias elicited by interaction between acute myocardial ischemia and sympa- thetic hyperactivity: A new experimental model for the study of antiarrhythmic drugs. Cardiovasc Pharmacoll98 1;

Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of the heart. Circulation 1990;

Currie P, Ashby D, Saltissi S. Prognostic significance of transient myocardial ischemia on ambulatory monitoring after acute myocardial infarction. Am J Cardiol 1993;71:773- 777.

1997; 18:789-797.

1991;65:14-19.

653 - 657.

311251- 1259.

82:1095- 1105.


19. Quintana M, Lindvall K, Carlens P, et al. ST-segment depression on ambulatory electrocardiography in the early in- hospital period after acute myocardial infarction predicts early and late mortality: A short-term and a 3-year follow- up study. Clin Cardiol 1995; 18:392-400.

20. Albrecht P, Cohen RJ. Estimation of heart rate power spectrum bands from real-word data: Dealing with ectopic beats and noisy data. Comput Cardiol 1988; 15:311-314.

21. Nygirds ME. An automated system for ECG monitoring. Comput Biomed Res 1978; 12:181-202.

22. Kay SM, Marple SL. Spectrum analysis a modern perspec- tive. Proc IEEE 1981;69:1380- 1419.

23. Bigger JT, Fleiss JL. Stability over time of heart period variability in patients with previous myocardial infarction and ventricular arrhythmias. Am J Cardiol 1992; 69:718- 723.

24. Quintana M, Lindvall K, Brolund F, et al. Prognostic value of exercise stress test versus ambulatory electrocardiography after acute myocardial infarction: A three-year follow- up study. Coron Artery Dis 1995;6:865-873.

25. Singh N, Mironov D, Armstrong PW, et al., for the GUSTO ECG Substudy Investigators. Circulation 1996; 93: 1388 - 1395.

26. Bigger JT, Hoover CA, Steinman RC, et al. Autonomic nervous system activity during myocardial ischemia in man estimated by power spectral analysis of heart period variability. Am J Cardiol 1990; 66:497-498.

27. Bjorkander I, Held C, Forslund M, et al. Heart rate variability predicts cardiac events in patients with stable angina pectoris. /abstract) Eur Heart J 1997; 18:3455.

28. Hayano J , Yamada A, Mukai S, et al. Severity of coronary atherosclerosis correlates with the respiratory component of heart rate Variability. Am Heart J 1991; 121:1070- 1079.

29. Pozzati A, Pancaldi LG, DiPasquale G, et al. Transient sympathovagal imbalance triggers "ischemic" sudden death in patients undergoing electrocardiographic Holter monitoring. J Am Coll Cardiol 1996; 27:847- 852.

30. Goseki Y, Matsubara T, Takahashi N, et al. Heart rate variability before the occurrence of silent myocardial ischemia during ambulatory monitoring. Am J Cardiol 1994; 73:845- 849.

31. Vardas PE, Kochiadakis GR, Manios EG, et al. Spectral analysis of heart rate variability before and during episodes of nocturnal ischemia in patients with extensive coronary artery disease. Eur Heart J 1996; 17:388-393.

32. Gill JB, Cairns JA, Roberts RS, et al. Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction. N Engl J Med 1996;

33. Farrell TG, Bashir Y, Cripps T, et al. Risk stratification for 334:65 - 70.

arrhythmic events in post-infarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram. J Am Coll Cardiol 1991; 18:687-697.

34. Bayes de Luna A, Coumel P, Leclercq JF. Ambulatory sudden death: Mechanism of production of fatal arrhythmias on the basis of data from 157 cases. Am Heart J 1989; 117

35. Martin GJ, Magid NM, Myers G, et al. Heart rate variability and sudden death secondary to coronary artery disease during ambulatory electrocardiographic monitoring. Am J Cardiol 1987;60:86-89.

36. Vybiral T, Glaeser DH, Goldberger AL, et al. Conventional heart rate variability analysis of ambulatory electrocardiographic recordings fails to predict imminent ventricular fibrillation. J Am Coll Cardiol 1993;22:557- 565.

37. Langer A, Minkowitz J, Dorian P, et al. Pathophysiology and prognostic significance of Holter-detected ST segment depression after myocardial infarction. J Am Coll Cardiol

38. The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lan- cet 1990;336:827-830.

39. Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group. Low molecular weight heparin during instability in coronary artery disease. Lancet 1996; 335:

40. Yoshio H, Shimizu M, Sugihara N, et al. Assessment of autonomic nervous activity by heart rate spectral analysis in patients with variant angina. Am Heart J 1993; 125:324- 329.

41. Quintana M, Lindvall K, Brolund F, et al. Markers of risk after acute myocardial infarction. A comparison of clinical variables, ambulatory and exercise electrocardiography, echocardiography and stress echocardiography. Coron Ar- tery Dis 1997;8:327-334.

42. Dellborg M, Malmberg K, RydCn L, et al. Dynamic on-line vectorcardiography improves and simplifies in-hospital ischemia monitoring of patients with unstable angina. J Am Coll Cardiol 1995;26:1501- 1507.

43. Krucoff MW, Croll MA, Pope JE, et al., for the TAMI 7 Study Group. Continuous 12-lead ST-segment recovery analysis in the TAMI study. Performance of a noninvasive method for real-time detection of failed myocardial reperfusion. Circulation 1993; 88:437-446.

44. Lundin P, Eriksson SV, Fredriksson M, et al. Prognostic information from on-line vectorcardiography in unstable angina pectoris. Cardiology 1995; 86:60-66.

151- 159.

1992;20:1313- 1317.

561-568.

Documents

The Association Between Residual Myocardial Ischemia and Heart Rate Variability Early After Acute Myocardial Infarction