silent myocardial ischemia as a potential link between lack of premonitoring symptoms and increased...

Silent Myocardial lschemia as a Potential Link Between Lack of Premonitoring

Symptoms and Increased Risk of Cardiac Arrest During Physical Stress

Eike Hoberg, MD, Gerhard Schuler, MD, Bernd Kunze, RA, Anne-Liese Obermoser, RN, Klaus Hauer, Hans-Peter Mautner, MD, Gilnter Schlierf, MD,

and Wolfgang KUbler, MD

The risk of cardiac arrest is increased during strenuous physical exercise in patients with stable coronary artery disease (CAD). Because premonitoring symptoms are rarely observed, silent myo- cardiil ischemia may represent the pathophysidog- ieal basis for the inciuction of malignant ventricular arrhythmias. Hotter monitoring was, therefore, performed in 40 consecutive patients entering a randomized intervention trial on progression of CAD. In 20 of 21 participants (95%) in the intervention program 21 episode of silent myocardial ischemia was observed during the initial training session. The mean duration of silent myocardial ischemia per patient was 25 l 13 min/hr of training session. During normal daily activity only 5 patients (24%) experienced 21 episode of silent myocardial ischemia (p <O.OOl) yiekling a mean duration of 0.6 f 1.3 minutes of silent myocardial ischemia/hr of ordinary activity per patient (p <O.OOl vs training session). During a control period of 24 hours without exercise training the incidence (33%) and mean duration of silent myocardial ischemia (0.8 f 2.1 min/hr/patient) were similar to those during normal daily activity on the day of the training session. During the training session the occurrence of frequent or repetitive ventricular arrhythmias was related to 10 silent myocardial ischemia episodes detected in 5 patients. During normal daily activity in 1 patient only was the onset of malignant ventricular arrhythmias associated with silent myocardial ischemii (p <O.OS). Conditions and results of the Holter studies in the control group patients were comparable to those of the patients in the intervention group on the day without physical exercise.

Silent myocardial is&en&related malignant ventricular arrhythmias can be provoked by physical stress in a substantial subset of patients with clinically stable CAD. Hence, siknt myocardial ischemia may be the missing link between the increased risk of cardiac arrest and the lack of premonitoring symptoms during supervised exercise in cardiac rehabilitation programs.

(Am J Cardiol 1990;65:663-669)

I ndividually adjusted physical exercise is a mainstay of most secondary prevention programs for coronary artery disease (CAD). The salutary effects have

been documented by several clinical studies.l-5 In addition to improving exercise tolerance by peripheral adap- tive changes,5,6 stress-induced myocardial ischemia it- self seems to be affected beneficially.3x4 The incidence of exertion-related cardiac arrest is increased during supervised training sessions of cardiac rehabilitation programs compared to other activities of the participantsa According to experimental studies, life-threatening ventricular tachyarrhythmias can be initiated and main- tained during early myocardial ischemia.8,9 Cardiac arrest may be induced by moderate to strenuous physical exercise in CAD patients, yet premonitoring symptoms have rarely been reported.7 Hence, silent myocardial ischemia could provide a link between exertion-related cardiac arrest and missing premonitoring symptoms. The aim of this study was, therefore, to determine the frequency of malignant ventricular arrhythmias that are related to silent myocardial ischemia during supervised exercise training sessions and during normal daily activity.

METHODS Patient population: The study group consisted of 40

male patients aged 43 to 64 (mean 54) years, who were participating in a randomized trial of the influence of regular physical exercise and low fat diet on the progression of CAD. Patients were selected only after coronary angiography was performed. Inclusion criteria were: male sex, age <65 years, proven CAD (>70% stenosis of 21 major vessel) and willingness to partici- pate in the intervention program for 212 months. Ex- clusion criteria consisted of previous coronary bypass surgery or coronary angioplasty, left main CAD, severe- ly depressed left ventricular function (ejection fraction

From the Abteilung fnnere Medizin 111 (Schwerpunkt Kardiologie, Angiologie und Pulmologie). University of Heidelberg, Heidelberg, West Germany. This study was supported in part by a grant from Bundesministerium fiir Forschung und Technologie. Bonn, West Ger- many. Manuscript received June 28. 1989: revised manuscript received and accepted November 6. 1989.

Address for reprints: Eike Hoberg. MD. Abteilung Innere Medizin III. MediLinische Univeraitdtbklinik, Bergheimer Strassc 58. D-6900 Heidelberg, West German)

THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 1, 1990 583

TABLE I Patient Characteristics

- .--

Intervention Group Control Group (n = 21) (n = 17)

Age Ws) 53 f 5 54*7

Vessels involved (n) 2.0 f 0.7 1.9 f 0.7 RNV EF (%) 54flO 51 f9

A RNV EF (%) -0.4 f 6.9 2.1 f 10.5

Previous MI (n) 0.7 f 0.5 0.8 f 0.6

Max workload (watts)’ 146 f 30 163 f 29

Max heart rate (beats/min)* 148f18 151f15

Max HR X BP (mm Hg/min X l.OOO)* 27 f 7 28f5 Gensini score 36 f 22 54f45

Patients taking fl blockers 12 7

Patients taking calcium antagonists 9 7

Patients taking nitrates 11 9

* Dwng symptom-llmited bicycle exercise testing upon entry into the study. BP = blood pressure: EF = ejection fraction: HR = heart rate; MI = myocardlal Infarction; NS = not slgnlbcant: RNV = radlonuclide ventnculography.

p Value

NS NS

NS NS NS NS NS

NS NS NS NS

NS

<35%), congestive heart failure, valvular heart disease, uncontrolled hypertension, insulin-dependent diabetes mellitus, primary hypercholesterolemia (low density li- poprotein >210 mg/dl) or presence of disabling noncar- disc disease.

After informed consent was obtained, patients were randomized to either a control group, which received usual care according to present guidelines (n = 19), or an intervention group (n = 21). The intervention program was based on a low fat diet and regular physical exercise consisting of supervised group training sessions twice a week and bicycle ergometer training for 10 minutes once daily, individually adjusted to 75% of the symptom-limited maximal heart rate. Antianginal therapy, including nitrates, /3 blockers and calcium antagonists, was prescribed as necessary. No patient received digitalis glycosides within 4 weeks before entry into the study. Patients in the control group did not differ significantly from those in the intervention group with respect to age, number of obstructed vessels, coronary score (Gensini),lO left ventricular ejection fraction, history of prior myocardial infarctions, exercise electrocardiogram parameters or antianginal therapy (Table 1). Two pa-

tients in the control group were excluded from the Holter studies, due to constant or intermittent left bun- dle branch block.

Hdter monitoring: Frequency modulated Holter monitoring (Oxford Me&log 2-FM) of leads CM=, and CC5 was performed within 2 weeks after entry into the study. In the intervention group the two 24-hour monitoring periods were on the day of the first group training session and a training-free day. The control group was investigated during ordinary activity. Patients were asked to keep a detailed diary of their activities and symptoms. Calibrated tapes (Oxford Z.M-2) were re- played at 60 times normal speed. The playback unit (Oxford PB 4) was linked to a Pathfinder Holter electrocardiogram analyzer (Reynolds Medical). ST-segment analysis was based on high resolution trend recordings of relative ST-segment deviation and heart rate (Trend System, Reynolds Medical), as described in detail previously. ’ ’ Episodes were interpreted to indicate myocardial ischemia when ST-segment elevations or horizontal or downsloping ST-segment depressions LO. 1 mV were observed for I1 minute. Whenever the differentiation between upsloping and horizontal ST segment

T ***

Intervention Group

Control Group

Day of initial

T T T 1

1 A

training session

I 1 Control day

en//i/ //n[

Training session Normal activity

FIGURE 1. Mean duation of silent myo- cadlll ischemia duing the training session and ordinary activity in the interven- tbn group (open bars) and in the control gmup (hd&ed bars). * * * Buring thfi tralnlng sosslon the dvatlon of silent myocardial is&em& was ~fkantiy lagor (p <O.ool) compared to the othsr 3mltdwingperiods.

584 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

depressions was impeded by artifacts or high heart rates, only episodes of 2 10 consecutive complexes with clearly horizontal ST-segment depressions were accepted as expression of myocardial ischemia.

Computer-assisted analysis of ventricular arrhythmias (Pathfinder 3, Reynolds Medical) was double- checked by full disclosure electrocardiographic print- outs (32 cm/min) analyzed by 2 experienced investiga- tors. For summation of single premature ventricular contractions ventricular bigeminy was not taken into ac- count. Ischemia-related malignant ventricular arrhythmias were defined as an abrupt increase in the rate of premature ventricular contractions (22 standard deviations compared to lo-minute intervals during the pre- ceding 2 hours) resulting in frequent (>5 single premature ventricular contractions/min) or repetitive (22 consecutive premature ventricular contractions, RR interval 1600 ms) ventricular arrhythmias-or onset of abrupt increase in premature ventricular beat rate after 130 seconds of significant ST-segment deviations.

Radionuclide vewtriculography: Gated blood pool cardiac scintigraphy was performed with patients in the horizontal position at rest and during maximal symptom-limited exercise. Left ventricular ejection fraction was calculated by computer analysis as previously described.‘*

Statistical analysis: For statistical evaluation non- parametric tests (the Mann-Whitney U test for compar-

FIGURE 2. High l-oduthtrolldlvxord- ings(paperspeed3Ocmhr)(top)adfuW di-~(bofrom)ofthoRdtor

F&m-T*b =WY

was pmcodod by signmant ST-sogmsol dofmdamaftoranabrupt-In hoarlrato(*).Tho6rst2silontisdwmk OpbOdOSWithST~~UhtWSOf upto0.6mVdwingthetrahingseAon weronotassecModwlth~ an+nythmlas.

isons of the control group with the intervention group, the Wilcoxon signed-rank test for intraindividual com- parisons and Fisher’s exact test) were used.13

RESULTS Incidence of silent ischemia: During the day of the

initial training session 20 of 21 patients (95%) in the intervention group developed 21 episode of silent myocardial ischemia. Only 7 of the participants (33%) in the intervention program had silent myocardial ischemia during the control day (p <O.OOl). Similarly, the number of episodes of silent myocardial ischemia was higher on the day of the first training session than on the control day (67 vs 28, p KO.01). This difference was due to an increased incidence of silent myocardial ischemia during the training session (2.3 f 1.3 episodes/hr/ patient); during normal daily activities the mean number of silent myocardial ischemia episodes/hr was comparable on both the training and control days (0.06 f O.l2/patient on the traning day vs 0.09 f O.l7/patient on the control day, difference not significant).

Four of 17 patients (24%) in the control group developed a total of 24 episodes of silent myocardial ischemia during ordinary daily activities. Hence, the incidence of silent myocardial ischemia in the control group (0.09 f 0.2 episodes/hr/patient) did not differ significantly from that of the intervention group during normal daily activities. It was, however, markedly lower


TABLE II Characteristics of Patients With and Without Silent Myocardial Ischemia-Related Ventricular Arrhythmias During the First Training Session (Intervention Group)

Ischemia-Related Ventricular Arrhythmias

Age Ws) Vessels involved (n) RNV EF (%) A RNV EF (%) Previous Ml (n) Max HR X BP (mm Hg/min X l.ooO)* Gensini score Patients taking fl blockers (%)

* During symptom-limited bicycle exercise upon entry into the study. Abbreviations as in Table I.

Present Absent (n = 5) (n = 16)

53 f 5 54f7 2.0f 1.0 2.1 f0.7 55 f 3 53f 11

-5flO lf5 0.2 f0.2 0.8f0.5 24f7 28f5 37f40 36f14

100 81

p Value

NS NS NS NS -Co.05 NS NS NS

compared to the incidence of silent myocardial ischemia intervention group (24%); they were associated with fre- during the training session (p <O.OOl). Neither the pa- quent or repetitive ventricular arrhythmias. Six of these tients in the intervention group nor the patients in the episodes were characterized by an abrupt increase in the control group demonstrated any episode of silent myo- premature ventricular beat rate. During 3 episodes of cardial ischemia during bed rest. silent myocardial ischemia the occurrence of couplets or

The mean duration of ischemic episodes was similar triplets was observed as was an increased frequency of under all conditions in both patient groups. Duration of single premature ventricular contractions. One patient silent myocardial ischemia was, therefore, markedly developed silent myocardial ischemia-related nonsus- longer during the initial exercise training (25 f 13 min/ tained ventricular flutter (Figure 2). In all of the 5 pa- hr/patient) compared to normal daily activity on the tients additional episodes of myocardial ischemia not as- day of the first training session (0.6 f 1.3 min/hr/pa- sociated with ventricular arrhythmias were observed. tient, p <O.OOl), or on the training-free day (0.8 f 2.1 Repetitive ventricular arrhythmias were exclusively re- min/hr/patient, p <O.OOl), or in the control group (0.9 lated to silent myocardial ischemia during the training f 2.1 min/hr/patient, p <O.OOl) (Figure 1). sessions.

Ischemia-related malignant ventricular awhyth- In the 5 patients with silent myocardial ischemia- mias: During the training session 10 episodes of silent related ventricular arrhythmias the number of single myocardial ischemia were identified in 5 patients of the premature ventricular contractions was significantly

Single PVCS

1 pco.05 r5

patients with ““i~r~lat~d VA

”

q Training session

Normal activity

“.S 9-l ri EzzzLz4

Patients without S”li~~~9d VA

flGUBE 3. single premature wntrkdr contractIon (PVC) &wing training ses- slonsand normalactlvityinthe5pa6ents with slleni myocardial ischemla-related vontrla~lar ad~ytlmlas (MWrebbd VA) ad in the remaining 16patkntsinthein- toNon6ongrwp.Thapati8ntswlthslle!nt myacardial ischemia-related venthdar octopy had single premature ventrkular cxnedhsmoro~duringthe training session compl!vedtoother actM608 (p <0.65).


higher during the training session compared to normal activities (78 f 45 vs 3.3 f 4.2/hr/patient, p <0.05). In the remaining 16 patients in the intervention group the frequency of single premature ventricular contractions was similar on both occasions (4.7 f 9S/hr of training/patient vs 6.8 f 20.7/hr of normal activity/ patient, difference not significant) (Figure 3). In the training group, during normal daily activity on the training day only 1 episode of silent myocardial ischemia was detected that was accompanied by the onset of malignant ventricular arrhythmias (silent myocardial ischemia-related ventricular arrhythmias during training vs normal activity p <0.05). In this patient only another 3 silent myocardial ischemia episodes with malignant ventricular arrhythmias were identified on the training-free day (silent myocardial ischemia-related ventricular arrhythmias on the day of training vs training-free day, p <0.05). The incidence of silent myocardial ischemia-related ventricular arrhythmias in the control group (2 episodes in 1 patient) was comparable to that in the intervention group during the control day.

The 5 patients of the intervention group who exhib- ited silent myocardial ischemia-related ventricular arrhythmias did not differ significantly from the remaining 16 patients in this group with regard to left ventricular ejection fraction, number of obstructed vessels, coronary score, number of patients taking fi blockers, or maximal pressure-frequency product during bicycle ergometer testing (Table II). During exercise mean left ventricular ejection fraction decreased by 5 f 10% in the patients with ventricular arrhythmias, and increased by 1 f 5% in the patients without them (difference not

significant). The number of previous myocardial infarctions was smaller in the patients with ischemia-induced ventricular arrhythmias compared to the other patients in the intervention group. During stress testing on entry into the study, 1 patient developed intermittent ventricular bigeminy for 30 seconds on 25 watts of workload. In another patient single polymorphic premature ventricular contractions (<5/min) were observed on maximal workload (150 watts). On exercise testing none of the patients, however, met the criteria of silent myocardial ischemia-related malignant ventricular arrhythmias as defined.

Symptomatic ischemic episodes: In contrast to silent episodes, symptomatic episodes of myocardial ischemia were infrequent. During both 24-hour monitoring periods 4 patients in the intervention group developed 6 symptomatic episodes, 4 of which occurred during the training session. Two of these episodes were associated with frequent and repetitive ventricular arrhythmias in 1 patient. This patient also demonstrated silent myocardial ischemia-related ventricular arrhythmias. In 2 control group patients, 3 symptomatic episodes of ischemia were observed; none was related to silent myocardial ischemia.

DISCUSSION The results of this study imply a causal relation be-

tween silent myocardial ischemia and malignant ventricular arrhythmias in a subset of patients with clinically stable CAD. During a total of 2,698 hours of ordinary activity monitored in 38 patients with angio- graphically proven CAD, 6 of 71 episodes of silent myo-

Training Session Exercise Testing

Heart rate Heart rate

2 min

0-I I 1 I I

-j I

6 -4 -3 -2 -1 0 Time before onset of VA (min) Time before onset of VA (min)

I I I I

-5 -4 -3 -2 -1 0 +1 Time before and after tha end Time before and after the end

of stress testing of stress testing . . .

FIGURE 4. Time silent myacardial irdremia-related ventriahr ahythmiis (VA) during training sesshs (fen). Right shewr the time course of heart rata8 dving exercise testing in the same patknts. Compared to exercise testing, the aczeleration of heart rate thing training sessions was higher, resldting in a shorter time interval needed to reach the maximal heart rate.

THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 1. 1990 587

cardial ischemia (8%) detected in 2 patients (5%) were accompanied by an abrupt onset of frequent single premature ventricular contractions. During 21 hours of exercise training monitored in the 21 patients in the intervention group, 10 of 48 silent myocardial ischemia episodes (21%) observed in 5 patients (24%) were associated with frequent or repetitive premature ventricular contractions. Silent myocardial ischemia-related repetitive ventricular arrhythmias were exclusively observed during the training sessions. Hence, strenuous physical exercise obviously facilitates the occurrence of both silent myocardial ischemia and silent myocardial ischemia-related malignant ventricular arrhythmias.

The increased frequency of silent myocardial ischemia during the training sessions is due to increased myocardial oxygen demand. In all patients maximal heart rates during exercise training exceeded those during normal daily activity. During bicycle exercise testing, however, no ischemia-related malignant ventricular arrhythmias were observed. Additional factors may, therefore, be operating to trigger ventricular arrhythmias during training-related periods of silent myocardial ischemia. In the patients with malignant ventricular arrhythmias during training sessions, mean maximal heart rates during training and bicycle stress testing were comparable. The magnitude of ST-segment depression was also similar during these 2 conditions. Analysis of the acceleration of heart rates during exercise testing and training sessions may yield a possible explanation: during training sessions a maximal heart rate of 120 beatsjmin was reached within 2 minutes, whereas during exercise testing the same heart rate was reached only after 3.6 minutes (Figure 4). Accordingly, the acceleration of the heart rate was significantly greater during the training session compared to bicycle stress testing (32.8 f 8.8 vs 21.6 f 4.9 beats/min2, p <0.05). Experimental animal studies suggest that increased sympathetic activity may represent the media- tor for both the rapid increase in heart rate and the ischemia-related increased ectopic ventricular activity* 14-16

By use of 3-dimensional mapping Pogwizd and Corr9 showed that the initiation and maintenance of ventricular tachycardia during early ischemia is due to intramural reentry and to nonreentrant mechanisms. In clinical settings, the association between transient myocardial ischemia and malignant ventricular arrhythmias seems to be infrequent in patients with CAD without acute myocardial infarction: many ischemic episodes in large populations of patients with stable and unstable angina have been described without reference to related ventricular arrhythmias. In this study, during normal daily activity only 5% of the patients developed an abrupt increase in premature ventricular beat rate associated with significant ST-segment depression. So far, the potency of silent myocardial ischemia to induce ventricular arrhythmias has been demonstrated during Holter monitoring in only a few cases.17-20 In addition, Sharma et a121 found an 80% incidence of exercise-induced silent myocardial ischemia in 15 CAD patients who survived out-of-hospital ventricular fibrillation.


The occurrence of ventricular arrhythmias during silent myocardial ischemia, however, was not reported in these patients.

According to previous studies the risk of cardiac arrest is increased 6- to lo-fold during supervised training sessions of cardiac rehabilitation programs.9 The under- lying mechanism for induction of the life-threatening ventricular arrhythmias, however, remained unclear.22 In this study the incidence of silent myocardial ischemia-related malignant ventricular arrhythmias was increased 5-fold during training sessions. It is conceivable that silent myocardial ischemia may be causally related to the induction of ventricular arrhythmias in a sub group of CAD patients.

Limitations of the study: Horizontal or downsloping ST-segment depressions 10.1 mV during frequency- modulated Holter monitoring have been demonstrated to represent myocardial ischemia.23 During exercise training the identification of significant ST-segment depression was impeded by artifacts and high heart rates in some patients. The high resolution trend recordings of relative ST-segment deviations facilitated the detec- tion of episodic ST-segment depressions 10.1 mV under these conditions. The differentiation between upsloping and horizontal ST-segment depressions may still remain difficult. In this study only episodes of 110 consecutive complexes with clearly horizontal ST-segment depressions on the electrocardiographic printout were accepted as expression of myocardial ischemia. Hence, it cannot be excluded that the true number of ischemic episodes during the training session may be even higher-but not lower-than reported.

The definition used in this study for malignant ventricular arrhythmias is deduced from previous Holter studies in postinfarction patients: frequent single premature ventricular contractions (>lO/hr) have been identified as an independent risk factor for sudden death in 2 large multicenter trials.24,25 In our study, only 1 of the 5 patients in whom silent myocardial ischemia-related ventricular arrhythmias were identified presented with a history of previous myocardial infarction. Thus, the prognostic implications of the detected ventricular arrhythmias remain uncertain. Nevertheless, 1 patient collapsed during the training session due to nonsus- tained ventricular flutter associated with silent myocardial ischemia. This demonstrates the potential risk of silent myocardial ischemia-related ventricular arrhythmias.

Clinical implications: Upon entry in cardiac rehabilitation programs exercise testing is usually performed to fix individual limits of exertion. According to current reports, establishing such limits does not decrease the risk of cardiac arrest during training sessions.26-29 In the present study, none of the 5 patients developed ventricular arrhythmias during stress testing comparable to those observed on Holter monitoring during the training session. Even continuous electrocardiographic monitoring on a training-free day may be of little value for the identification of patients at special risk for cardiac arrest during training. On the other hand, Holter monitoring performed on the day of the first training session

identified a subgroup of patients with exercise-related ventricular arrhythmias. In the absence of angina1 pain ST-segment analysis demonstrated the association of these ventricular arrhythmias to episodes of silent myocardial ischemia. Holter monitoring on the day of the first training session may, therefore, represent the best method available at present for the identification of patients at special risk for exertion-related ventricular arrhythmias.

Acknowledgment: The expert Rausch, RA, Sabine Methfessel, mire1 is gratefully acknowledged.

assistance of Sabine RA, and Aynur De-

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