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(Chest. 2001;120:834-839.)
© 2001 American College of Chest Physicians

Diagnostic and Prognostic Value of Holter-Detected ST-Segment Deviation in Unselected Patients With Chest Pain Referred for Coronary Angiography*

A Long-term Follow-up Analysis

Chandra K. Nair, MD, FCCP; Ijaz A. Khan, MD; Dennis J. Esterbrooks, MD; Kay L. Ryschon, MS and Daniel E. Hilleman, PharmD

* From the Division of Cardiology, Department of Medicine, Creighton University School of Medicine, Omaha, NE.

Correspondence to: Chandra K. Nair, MD, FCCP, Creighton University Cardiac Center, 3006 Webster St, Omaha, NE 68131


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Objective: To evaluate the diagnostic and prognostic significance of ST-segment deviation detected by ambulatory Holter monitoring in unselected chest pain patients referred for coronary angiography.

Methods: Two hundred seventy-seven patients (71% were men) who underwent coronary angiography for evaluation of chest pain were studied with 24-h ambulatory Holter monitoring within 72 h of angiography. A lumen diameter reduction of >= 50% was considered coronary artery disease. The ST-segment deviation was defined as >= 1-mm deviation from the baseline lasting >= 1 min separated by a minimum of 1 min. The patients were followed up for 65 ± 21 months (mean ± SD) for occurrences of death, myocardial infarction, hospitalization for unstable angina, and need for revascularization.

Results: Of the 277 patients, 223 (80%) had coronary artery disease. The prevalence of coronary artery disease was not significantly different in patients with (43 of 48 patients; 90%) and without (180 of 229 patients; 79%) Holter-detected ST-segment deviation. The diagnostic accuracy of Holter-detected ST-segment deviation in predicting the presence of coronary artery disease was poor (33%), with a sensitivity of 19% and a specificity of 91%. The presence of Holter-detected ST-segment deviation was not predictive of future cardiac events or death.

Conclusion: The ST-segment changes detected on ambulatory Holter monitoring are of limited value in identifying coronary artery disease and predicting the future adverse cardiac events or death in unselected patients with chest pain.

Key Words: ambulatory ECG monitoring • coronary artery disease • diagnostic accuracy • ECG • Holter monitoring • ischemic heart disease • sensitivity • silent ischemia • specificity • ST segment


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
The ST-segment deviation detected by ambulatory ECG monitoring correlates well with the other objective measures used to define myocardial ischemia in patients with known coronary artery disease.1 2 3 4 5 6 7 8 9 10 11 The presence of ST-segment deviation during ambulatory ECG (Holter) monitoring in selected patients with stable angina pectoris, unstable angina, myocardial infarction, and aborted sudden cardiac death is also predictive of future cardiac events.9 10 11 12 13 14 15 16 However, limited data are available regarding the diagnostic and prognostic value of the Holter-detected ST-segment deviation in the unselected patients with chest pain referred for coronary angiography. Similarly, the diagnostic significance of the ST-segment deviation detected by ambulatory ECG monitoring is unknown in patients with baseline ST-segment changes known to affect ST-T wave interpretation, whereas exercise-induced ST-segment deviation is known to have a lower diagnostic yield in these patients.16

In this study, the diagnostic and prognostic significance of Holter-detected ST-segment deviation in unselected patients with chest pain referred for coronary angiography was determined, and was correlated with the extent and severity of coronary artery disease. The diagnostic and prognostic significance of Holter-detected ST-segment deviation was also compared between patients with baseline ST-segment changes known to affect ST-T wave interpretation and those without such changes.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patient Population
Two hundred seventy-seven consecutive patients with chest pain referred for coronary angiography at the Creighton University Medical Center were enrolled in this prospective study. All patients were characterized according to age, gender, history of myocardial infarction, previous revascularization procedures, standard risk factor assessment, concomitant disease status, drug therapy, and angina history. Patients were instructed to continue taking all of their medications, including digoxin and antianginal medications, during ambulatory ECG monitoring.

Study Protocol
The study was approved by the Institutional Review Board for Human Subjects Research of the Creighton University, and written informed consent was obtained from all participants. All study participants underwent continuous 24-h ambulatory ECG monitoring within 72 h after the coronary angiography.

Coronary Angiography:
Coronary angiography was performed using the Judkin’s approach. Multiple coronary angiograms were made in a variety of projections to ensure the lesion visibility and accuracy. Coronary stenosis was assessed visually and interpreted by two observers unaware of the results of the ambulatory ECG recordings. Significant coronary stenosis was defined as a decrease in lumen diameter of >= 50% in one or more of the major epicardial coronary arteries or their primary branches.

Ambulatory Monitoring:
Continuous 24-h ambulatory ECG recordings were made on new ferrous oxide tapes using time-coded, reel-to-reel recorders (model 447; Delmar Avionics; Irvine, CA). The frequency range from these amplitude-modified recorders was 0.05 to 100 Hz. Calibration was accomplished with 1-mV and 0.1-mV square waves using a multiphase calibrator simulating the ECG QRS-complex. A two-lead system (modified lead II and V5) was used with meticulous skin preparation. Electrode sites were verified for lead placement and signal amplitude using a transtelephonic modulator transmitter. Subjects kept a detailed diary of the activities performed and symptoms experienced during the 24-h monitoring period. Ambulatory ECG recordings were reviewed using a Cardio-Data Prodigy Scanner (Mortara Instrument; Milwaukee, WI) at 120 times real time. Significant ST-segment depression or elevation was defined as >= 1 mm ST-segment deviation occurring 80 ms after the J point, lasting for >= 60 s. The episodes of ST-segment deviation agreed on by two reviewers were considered as significant. Separation of one episode from another required that the ECG return to baseline for a minimum of 1 min. The total number of the ST-segment deviations and the total duration of the episodes were determined for each patient. The heart rates at the onset and at the time of maximal ST-segment deviation were recorded for each individual episode. The physicians performing ECG analyses were blinded to the coronary angiographic findings and clinical characteristics of the patients.

Follow-up:
Patients were prospectively followed up for a mean ± SD of 65 ± 21 months from the time of initial monitoring for occurrences of death, nonfatal myocardial infarction, hospitalization for unstable angina, and need for revascularization with coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, or any other transcatheter revascularization procedure. Hospital records, outpatient clinic records, and patient, family or primary physician’s interviews were used for confirmation of the events. Deaths were classified as cardiac or noncardiac. Myocardial infarction was diagnosed if two of the following three prospectively defined criteria were met: (1) ischemic type chest pain with duration > 20 min; (2) a diagnostic ECG, which consisted of ST-segment elevation of >= 1 mm in two or more anatomically contiguous leads or development of new left bundle branch block; (3) serum creatine kinase-MB level of > 5 ng/mL with a creatine kinase-MB relative index of > 2.5% in two consecutive serum samples. Unstable angina was diagnosed if ischemic type chest pain lasted for > 20 min in absence of the ECG or enzyme changes consistent with myocardial infarction.

Statistical Analysis
Data were presented as mean ± SD where appropriate. A statistical probability of < 0.05 was considered significant. The diagnostic accuracy of the ST-segment deviation was examined for all patients and for subgroups of patients with and without baseline ST-segment changes. The prognostic value of the ST-segment deviation was examined for all patients, Comparisons of the groups with and without ST-segment deviation were performed using the Student’s t test or Pearson’s {chi}2 where appropriate. All p values were corrected for multiple comparisons where appropriate. The diagnostic value of the presence of the ST-segment deviation for the detection of coronary artery disease was evaluated by calculation of sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy. The following calculations were used: sensitivity (%) = 100 x (true-positives)/(true-positives + false-negatives); specificity (%) = 100 x (true-negative)/(true-negatives + false-positives); positive predictive value (%) = 100 x (true-positives)/(true-positives + false-positives); and negative predictive value (%) = 100 x (true-negatives)/(true-negatives + false-negatives); and diagnostic accuracy (%) = 100 x (true-positives + true-negatives/total number of tests). All the statistical analyses were performed using computer software (SPSS version 7.0; SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Clinical Characteristics
The study group consisted of 277 patients (196 men), with a mean age of 63 ± 10 years (range, 32 to 84 years). Clinical characteristics of the patients with and without ST-segment deviation during Holter monitoring are summarized in Table 1 . The distribution of baseline characteristics was not different between the two study groups. Seventy-one patients had preexisting conditions affecting the ST segment; 44 patients were receiving digoxin, 1 patient had complete left bundle-branch block, 8 patients had left ventricular hypertrophy, 6 patients had permanent pacemakers implanted, and 12 patients had one or more of the above.


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  		Table 1. Baseline Clinical Characteristics of Patients With and Without Holter-Detected ST-Segment Deviation*

 
Angiographic Findings
Two hundred twenty-three patients (80%) had at least one vessel with >= 50% obstruction, and 54 patients (20%) had no significant coronary obstruction. Single-vessel, double-vessel, and triple-vessel disease was present in 92 patients (33%), 59 patients (21%), and 72 patients (26%), respectively. The prevalence of coronary artery disease in patients with ST-segment deviation was not significantly different than that in patients without ST-segment deviation (43 of 48 patients [90%] vs 180 of 229 patients [79%]; p = not significant [NS]). Similarly, there was no significant difference in the single-vessel, double-vessel, and triple-vessel disease between groups (Table 2 ).


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  		Table 2. Coronary Angiographic Findings in Patients With and Without Holter-Detected ST-Segment Deviation*

 
Ambulatory Holter ECG Findings
Forty-eight patients (17%) had one or more episodes of ST-segment deviation with a total of 120 episodes. Thirty-four patients had 90 episodes of ST-segment depression, and 17 patients had 30 episodes of ST segment elevation. The average duration of episodes of ST depression was 42 ± 60 min (range, 1 to 272 min). The magnitude of ST-segment depression ranged from 1.0 to 4.2 mm (mean, 2.0 ± 0.8 mm), and it was >= 1 mm in 21 patients and >= 2 mm in 13 patients. The average duration of ST-segment elevation episodes was 17 ± 21 min (range, 2.5 to 75.5 min). Magnitude of ST-segment elevation ranged from 1.0 to 6.0 mm (mean, 2.1 ± 1.5 mm).

Diagnostic Accuracy of Holter-Detected ST-Segment Deviation
The diagnostic accuracy of the ST-segment deviation detected by the ambulatory ECG monitoring in predicting the presence of coronary artery disease for all patients is given in Table 3 , and in patients with or without baseline ST-segment abnormalities in Table 4 . Of the 223 patients with coronary artery disease, 43 patients (24%) had ST-segment changes. Of the 54 patients without coronary artery disease, 5 patients (10%) had ST-segment changes. Correlation of the Holter-detected ST-segment deviation and the severity and location of obstructed coronary arteries is shown in Table 5 .


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  		Table 3. Diagnostic Accuracy of Holter-Detected ST-Segment Changes for Predicting Coronary Artery Disease in all Patients*

 

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  		Table 4. Diagnostic Accuracy of Holter-Detected ST-Segment Changes for Predicting Coronary Disease in Patients With vs Without Baseline ST-Segment Changes*

 

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  		Table 5. Correlation of Holter-Detected ST-Segment Changes With Severity of Disease and Coronary Artery Involved*

 
Prognostic Value of Holter-Detected ST-Segment Deviation
Presence of any ST-segment deviation (depression or elevation) was not significantly correlated with the future cardiac events or death (Table 6 ). During a mean follow-up of 65 ± 21 months, the incidence of cardiac events (cardiac death, nonfatal myocardial infarctions, hospitalization for unstable angina, and need for revascularization) was similar in patients with and without ST-segment deviation, and was not a function of presence or absence of baseline ST-segment abnormalities.


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  		Table 6. Correlation of Presence or Absence of Holter-Detected ST-Segment Changes With Adverse Cardiovascular Outcomes*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Experience with ambulatory ECG monitoring for myocardial ischemia has been associated with a highly variable sensitivity and specificity for the detection of coronary artery disease.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 The ST-segment changes consistent with ischemia have been observed during ambulatory ECG monitoring in 18 to 59% of the patients with known coronary artery disease, and have generally correlated well with the other objective tests used to detect myocardial ischemia.13 14 15 16 17 18 19 20 21 The highest prevalence of ambulatory ECG monitoring detected ST-segment changes have been reported in patients with multivessel disease, unstable angina, or a recent myocardial infarction.22 23 24 25 26 27 28 29 However, the diagnostic accuracy of the exercise stress testing in the patients with coronary artery disease is significantly greater than that observed with the ambulatory ECG monitoring.17 The sensitivity of the ambulatory ECG monitoring-detected ST-segment changes for detection of myocardial ischemia is low even in patients with triple-vessel or left main coronary artery disease. Presumably, this is because these patients are relatively inactive to avoid angina, and so their heart rates (and double products) are relatively low. This is undoubtedly a major limitation of ambulatory ECG monitoring as opposed to exercise stress testing in detecting myocardial ischemia.

The prevalence of the ST-segment changes detected during the ambulatory ECG monitoring in our patients with coronary artery disease was 24%. Although the specificities were high, the sensitivities and diagnostic accuracy of the ST-segment change during ambulatory ECG monitoring in our population were poor. This is generally consistent with other published reports.12 13 14 15 16 17 18 19 20 21 In our study, however, the presence of multivessel disease, unstable angina, or myocardial infarction was not associated with a higher prevalence of ambulatory ECG monitoring detected ST-segment changes, and ambulatory ECG monitoring also failed to predict the severity and location of the coronary artery stenosis, which is in discrepancy with some other published reports.12 13 14 15 16 17 18 19 20 21 These discrepancies between the results of our study and with other published reports may be due to the fact that our patient population consisted of unselected patients of chest pain.

Despite the relatively poor and erratic diagnostic value of the ambulatory ECG monitoring, the presence of the Holter-detected ST-segment changes in certain patient populations is highly predictive of future adverse cardiac events. In patients with stable angina, ST-segment changes detected by ambulatory ECG monitoring is an independent predictor of the adverse clinical events including death, myocardial infarction, and revascularization.12 13 14 15 16 17 18 19 20 21 In addition, the ambulatory ECG monitoring provides prognostic information additional to that derived from the established parameters obtained during exercise testing.13 18 29 Ischemia detected by the ambulatory ECG monitoring in patients with unstable angina or myocardial infarction has also been shown to be predictive of the future adverse clinical outcomes.25 26 27 28 29 However, the presence of ST-segment changes in our population was not predictive of future adverse clinical outcomes. We believe this occurred as our population consisted of unselected patients with chest pain.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
The ST-segment changes detected on ambulatory ECG monitoring in unselected patients with chest pain are of limited value in identifying the coronary artery disease and predicting the future adverse cardiac events including death, myocardial infarction, need for hospitalization for unstable angina, and revascularization.


   Footnotes
 
Abbreviation: NS = not significant

Received for publication December 4, 2000. Accepted for publication March 21, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Campbell, S, Barry, J, Rocco, MB (1986) Features of the exercise test that reflect the activity of ischemic heart disease out of hospital. Circulation 74,72-80[Abstract/Free Full Text]
  2. Mulcahy, D, Keegan, J, Crean, P, et al (1988) Silent myocardial ischemia in chronic stable angina: a study of its frequency and characteristics in 150 patients. Br Heart J 60,417-423[Abstract/Free Full Text]
  3. Panza, JA, Quyyumi, AA, Diodati, JG, et al (1991) Prediction of the frequency and duration of ambulatory myocardial ischemia in patients with stable coronary artery disease by determination of the ischemia threshold from exercise testing: importance of the exercise protocol. J Am Coll Cardiol 17,657-663[Abstract]
  4. Valle, GA, Lemberg, L (1990) Silent ischemia: a clinical update. Chest 97,186-191[Abstract/Free Full Text]
  5. Deanfield, J, Shea, M, Ribiero, P (1984) Transient ST-segment depression as a marker of myocardial ischemia during daily life. Am J Cardiol 54,1195-1200[CrossRef][ISI][Medline]
  6. Hirzel, H, Leutwyler, R, Krayenbuehl, H (1985) Silent myocardial ischemia: hemodynamic changes during dynamic exercise in patients with proven coronary artery disease despite absence of angina pectoris. J Am Coll Cardiol 6,275-284[Abstract]
  7. Levy, R, Shapiro, LM, Wright, C (1986) The hemodynamic significance of asymptomatic ST-segment depression assessed by ambulatory pulmonary artery pressure monitoring. Br Heart J 56,526-530[Abstract/Free Full Text]
  8. Selwyn, A, Allen, R, L’Abbotte, L (1982) Relationship between regional myocardial uptake of rubidium-82 and perfusion: absolute reduction of cation uptake in ischemia. Am J Cardiol 50,112-121[CrossRef][ISI][Medline]
  9. Mulcahy, D, Husain, S, Zalaz, G (1997) Ischemia during ambulatory monitoring as a prognostic indicator in patients with stable coronary artery disease. JAMA 277,318-324[Abstract]
  10. Sharaf, BL, Williams, DO, Miele, NJ (1997) A detailed angiographic analysis of patients with ambulatory electrocardiographic ischemia: results from the asymptomatic cardiac ischemia pilot (ACIP) study angiographic core laboratory. J Am Coll Cardiol 79,78-84
  11. Narins, CR, Zaretra, W, Moss, AJ, et al (1997) Clinical implications of silent versus symptomatic exercise-induced myocardial ischemia in patients with stable coronary disease. J Am Coll Cardiol 29,756-763[Abstract]
  12. Deedwania, P, Carbajal, E (1990) Silent ischemia during daily life is an independent predictor of mortality in stable angina. Circulation 81,748-756[Abstract/Free Full Text]
  13. Deedwania, P, Carbajal, E (1991) Usefulness of ambulatory silent myocardial ischemia added to the prognostic value of exercise test parameters in predicting risk of cardiac death in patients with stable angina pectoris and exercise induced myocardial ischemia. Am J Cardiol 68,1279-1286[CrossRef][ISI][Medline]
  14. Rocco, M, Nabel, E, Campbell, S (1988) Prognostic importance of myocardial ischemia detected by ambulatory monitoring in patients with stable coronary artery disease. Circulation 78,877-884[Abstract/Free Full Text]
  15. Yeung, A, Barry, J, Orav, J (1991) Effect of asymptomatic ischemia on long-term prognosis in chronic stable coronary disease. Circulation 83,1598-1604[Abstract/Free Full Text]
  16. Kennedy, HL (1992) Importance of the standard electrocardiogram in ambulatory (Holter) electrocardiography. Am Heart J 123,1660-1677[CrossRef][ISI][Medline]
  17. Crawford, MH, Mendoza, CA, O’Rourke, RA, et al (1978) Limitations of continuous ambulatory electrocardiogram monitoring for detecting coronary artery disease. Ann Intern Med 89,1-5
  18. Tzivoni, D, Gavish, A, Zin, D, et al (1988) Prognostic significance of ischemic episodes in patients with previous myocardial infarction. Am J Cardiol 62,661-664[CrossRef][ISI][Medline]
  19. Raby, KE, Goldman, L, Cook, EF, et al (1990) Long-term prognosis of myocardial ischemia detected by Holter monitoring in peripheral vascular disease. Am J Cardiol 66,1309-1313[CrossRef][ISI][Medline]
  20. de Marchena, E, Asch, J, Martinez, J, et al (1994) Usefulness of persistent silent myocardial ischemia in predicting a high cardiac event rate in men with medically controlled, stable angina pectoris. Am J Cardiol 73,390-392[CrossRef][ISI][Medline]
  21. Madjlessi-Simon, T, Mary-Krause, M, Fillette, F, et al (1996) Persistent transient myocardial ischemia despite beta-adrenergic blockade predicts a higher risk of adverse cardiac events in patients with coronary artery disease. J Am Coll Cardiol 27,1586-1591[Abstract]
  22. Deedwania, PC, Carbajal, EV (1991) Silent myocardial ischemia: a clinical perspective. Arch Intern Med 151,2373-2382[Abstract]
  23. Deedwania, PC, Carbajal, EV (1990) Prevalence and patterns of silent myocardial ischemia during daily life in stable angina patients receiving conventional antianginal drug therapy. Am J Cardiol 65,1090-1096[CrossRef][ISI][Medline]
  24. Cohn, PF (1986) Silent myocardial ischemia: dimensions of the problem in patients with and without angina. Am J Med 80,3-8[ISI][Medline]
  25. Gottlieb, SO, Weisfeldt, ML, Ouyang, P, et al (1986) Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med 314,1214-1219[Abstract]
  26. Currie, P, Ashby, D, Saltissi, S (1993) Prognostic significance of transient myocardial ischemia on ambulatory monitoring after acute myocardial infarction. Am J Cardiol 71,773-777[CrossRef][ISI][Medline]
  27. Gottlieb, SO, Gottlieb, SH, Achuff, SC, et al (1988) Silent ischemia on Holter monitoring predicts mortality in high-risk postinfarction patients. JAMA 259,1030-1035[Abstract]
  28. Deedwania, PC (1993) Asymptomatic ischemia during predischarge Holter monitoring predicts poor prognosis in the postinfarction period. Am J Cardiol 71,859-861[CrossRef][ISI][Medline]
  29. Gill, JB, Cairns, JA, Roberts, RS, et al (1996) Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction. N Engl J Med 334,65-70[Abstract/Free Full Text]



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