Diagnostics

Early detection and diagnosis of acute myocardial infarction: the potential for improved care with next-generation, user-friendly electrocardiographic Body surface mapping

Cedric Lefebvre MD?, James Hoekstra MD

Department of Emergency Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA

Received 26 April 2007; revised 18 June 2007; accepted 19 June 2007

Abstract Prompt and accurate identification of patients with acute coronary syndrome (ACS) presenting to the emergency department (ED) is paramount to the success of interventional and therapeutic strategies. Accurate diagnosis of ST-segment elevation myocardial infarction or Non-ST-segment elevation myocardial infarction is hindered by atypical presentations and suboptimal diagnostic tools. The current standard of care, 12-lead electrocardiogram, has limited efficacy. It does not allow complete imaging of various anatomic segments of the heart and therefore fails to accurately identify some patients who would benefit from immediate therapy. Body surface mapping (BSM) allows greater spatial representation of cardiac electrical activity than 12-lead electrocardiogram, with a more complete view of cardiac electrophysiology and greater sensitivity for detecting acute myocardial infarction. Recent technological advances have overcome previous limitations of BSM, including the need for extensive training, difficulty interpreting results, and cost. The future of BSM in the ED is not yet known but will be aided by the ongoing large-scale Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction trial (OCCULT-MI) trial, which uses PRIME BSM technology.

(C) 2007

Introduction

Cardiovascular disease is a leading cause of morbidity and mortality in American adults. Within the spectrum of acute coronary syndrome (ACS), acute myocardial infarc- tion (AMI) is a particularly severe health event associated with significant death and disability. An estimated 700000 Americans will have an AMI and 500000 will experience a recurrent MI each year [1]. For this reason, AMI has

* Corresponding author. Tel.: +1 336 716 4629.

E-mail address: [email protected] (C. Lefebvre).

become the focus of aggressive diagnostic and treatment algorithms. Yet despite advances in pharmacologic and invasive strategies to treat AMI, mortality associated with this phenomenon approaches 38% within the first year [2]. This may be due in part to the loss of valuable time from onset of symptoms to treatment, with the rate-limiting factor in many cases being identification and diagnosis of AMI.

Guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) highlight the importance of rapid identification and treatment of AMI, specifically ST-segment elevation myocardial infarction

0735-6757/$ – see front matter (C) 2007 doi:10.1016/j.ajem.2007.06.011

(STEMI) [3]. Class I recommendations for STEMI include acquisition and interpretation of a 12-lead electrocardiogram within 10 minutes of emergency department (ED) arrival, administration of Fibrinolytic therapy within 30 minutes of arrival, and/or percutaneous coronary interven- tion (PCI) within 90 minutes of arrival [3]. Several clinical trials have shown that early treatment and/or intervention in patients with STEMI affords the maximum benefit [4-9]. These data and subsequent ACC/AHA recommendations have driven health systems nationwide to implement guide- line-based protocols to rapidly identify and treat AMI. Patients with AMI who are not immediately identified by ST- segment deviation, however, often experience delays to diagnosis and subsequent pharmacologic intervention and PCI [10]. This delay precludes access to the benefits of early treatment, namely, preservation or restoration of Thrombo- lysis in Myocardial Infarction grade 3 flow in the infarct- related artery. Studies have shown that refractory/recurrent ischemia and delay to reperfusion imparts a negative impact on survival in patients with AMI [8,9,11-13]. Therefore, improvements are needed in the techniques used to identify

AMI so that treatment of this cardiac event can be initiated more quickly.

Current paradigm of AMI diagnosis

Presently, physicians make the diagnosis of AMI by using several diagnostic tools, including the 12-lead ECG, cardiac biomarkers, and clinical judgment. Fig. 1 depicts the current paradigm of AMI diagnosis. Unfortunately, each diagnostic tool has limitations. Cardiac biomarkers are highly sensitive and specific for the detection of myocardial injury but often take several hours from onset of injury to become elevated [14-17]. Their sensitivity for AMI in the ED setting approximates only 40% at presentation. This precludes their use for directing early pharmacologic and interven- tional therapies in the setting of AMI.

Conversely, a 12-lead ECG can be obtained within minutes of patient presentation to the ED and is therefore the cornerstone in the initial evaluation for STEMI and

Fig. 1 Current paradigm of AMI diagnosis. TIMI indicates Thrombolysis in Myocardial Infarction.

cardiac ischemia. Unfortunately, initial 12-lead ECG is not highly sensitive for the detection of these events. Several studies have shown that the sensitivity of initial ECG (positive identification of AMI) ranges from 34% to 56% when evaluating a patient presenting with ACS symptoms [18-21]. In addition, confounding factors such as left bundle- branch block (LBBB), left ventricular strain, or other baseline ECG abnormalities may complicate ECG interpretation, further diminishing its sensitivity for AMI. This is especially evident in patients with bundle-branch blocks (BBBs). Despite the development of diagnostic algorithms to improve the diagnostic sensitivity of the ECG in the setting of LBBB (ie, the Sgarbossa criteria), current diagnostic practice remains inadequate in the setting of confounding electro- physiologic variables to reliably identify AMI by ECG [22- 26]. Patients with AMI and LBBB generally have a worse prognosis compared to those without LBBB [27]. These patients develop more complications such as congestive heart failure and Lethal arrhythmias [28]. Go et al demonstrated that AMI patients with BBB patterns, in addition to having more comorbidities, are less likely to receive thrombolytic therapy. This group also carries a higher incidence of in-hospital mortality. In fact, AMI patients with LBBB and RBBB patterns had a 22% and 23% risk for in-hospital death, respectively, compared with a mortality rate of 13% for patients without BBB [29]. Failure of ECG to detect STEMI because of confounding BBB patterns further limits the sensitivity of this Diagnostic modality and may diminish the benefit of early treatment strategies.

Acquisition of serial ECGs has been proposed to increase the sensitivity of the ECG in the detection of AMI. The ACC/AHA guidelines include a class I recommendation to obtain serial ECGs in a patient with symptoms of ongoing cardiac ischemia/infarction if the initial ECG does not reveal evidence of STEMI [3]. Serial ECGs may improve sensitivity in the detection of AMI as demonstrated by a prospective trial by Fesmire et al [19] in which serial 12-lead ECG, obtained about 47 minutes after arrival to the ED, identified injury in an additional 16% of patients with AMI. Other studies, however, demonstrated modest benefit from serial ECGs in the evaluation of non-STEMI (NSTEMI) and low-to-intermediate risk patients with ACS [30,31]. The combination of serial ECG and serial cardiac biomarkers at 2-hour intervals may also increase sensitivity for the detection of AMI [32]. Interestingly, when dynamic ECG changes were identified over time, patients with these changes had a significantly greater risk of death compared to those without such changes [19,30]. These data suggest that sensitivity of current diagnostic tools improves during recurrent ischemia or during the evolution of infarction. Acquisition of serial ECGs and serial biomarkers requires hours of valuable time. As mentioned, rates of adverse cardiac events and mortality increase with time elapsed from onset of symptoms to early therapy. Thus, early treatment serves to limit infarct size during AMI, which correlates with improved outcome [33,34]. This appears to be particularly

true in high-risk subgroups, such as patients with diabetes [35-37]. If less time is allocated to the Diagnostic approach of ACS, more time could be allotted to the aggressive treatment of AMI, which would undoubtedly improve outcomes. Therefore, it is important to use diagnostic methods with greater sensitivity that can identify patients with AMI earlier in their course so that they may benefit from early therapy. A more accurate method is needed for rapid identification of AMI in patients with chest pain presenting to the ED.

Consequences of missed AMI by ECG

Without tools to more accurately and immediately identify AMI in patients with chest pain without ST elevation, current practice guidelines rely on risk stratifica- tion to direct early treatment. Because the risk of death and nonfatal cardiac events is highest during initial presentation and subsequent hospitalization, ACC/AHA guidelines use risk stratification to direct early therapy [38]. Despite these recommendations, however, Pharmacologic therapy has been underused. Furthermore, there appears to be a correlation between mortality and lack of adherence to ACC/AHA guidelines in the management of patients with NSTEMI [39-41]. Patients with NSTEMI may carry a higher rate of adverse outcomes than their counterparts with ST elevation because of delayed treatment [10]. And despite recent efforts to promote the use of upstream pharmacologic therapies, such as glycoprotein IIb/IIIa receptor inhibitors, in high-risk patients with NSTEMI, this patient group continues to experience delays to treatment [10,42]. Furthermore, there is emerging evidence that high-risk patients with NSTEMI might benefit from early invasive strategies [43,44]. If 12-lead ECG does not identify electrophysiologic patterns of ischemia or infarction in patients with chest pain, these patients may be inaccurately deemed nonspecific chest pain and may not receive appropriate early therapy. Missed ECG findings result in a loss of valuable time and preclude the benefit of early treatment.

In a retrospective analysis, Masoudi et al [45] illustrated the consequences of missed high-risk ECG findings on initial ECG. Patients with chest pain who were ideal candidates for treatments including aspirin, ?-blockers, and reperfusion therapy had higher odds of not receiving these therapies if initial high-risk ECG findings were overlooked. In-hospital mortality was 4.9% among patients without missed high-risk ECG findings compared with 7.9% for those with missed findings [45]. These interesting results suggest that, in addition to poor sensitivity of 12-lead ECG for capturing the data needed to identify AMI, human error in interpreting this data may further diminish our ability to diagnose AMI with initial ECG. The consequence of missing high-risk ECG findings and/or missing opportunities to treat high-risk patients with chest pain is costly. This exposes the

Fig. 2 A sample electrocardiograph (A); a picture of the output using PRIME BSM technology (B); and a coronary angiogram (C), all from one patient. Images used courtesy of the Royal Victoria Hospital, Belfast, Northern Ireland.

Fig. 2 (continued)

inadequacy of the current paradigm for identifying AMI and its significant consequences. The implications of inadequate ECG sensitivity on the initial evaluation of patients with chest pain translates to missed opportunities to treat high-risk patients who would benefit from aggressive therapy.

Body surface mapping and detection of AMI

Body surface mapping (BSM) is an extension of the conventional 12-lead ECG concept that may deliver improvements to the current diagnostic paradigm for AMI. Body surface mapping displays as a topographic map over a larger area of the thoracic surface, including the right ventricular (RV), posterior, and high left lateral regions. With 80 individual leads from which to measure electrocardio- graphic potentials, the BSM technique allows collection and analysis of data from a broader thoracic area, which allows for greater spatial sampling. The principles of BSM have been well established [46,47]. Until recently, however, its cumbersome electrode application and complex analysis of simultaneous multichannel ECG data have limited its use to the experimental research setting [48,49]. With the emer- gence of more user-friendly computer hardware/software and electrode application, BSM has now become feasible in clinical practice for the evaluation of patients with chest pain [48,50,51].

Several clinical trials have shown the efficacy and clinical relevance of a new generation of user-friendly BSM technology in the detection of AMI [52-56]. Body surface mapping has the potential to improve diagnostic evaluation of patients presenting with symptoms of AMI but on whom 12- lead ECG shows only ST depression. Menown et al prospectively evaluated validation-set patients with chest pain whose initial 12-lead ECG showed ST depression only. Investigators studied the ability of BSM to detect STelevation at sites outside the conventional precordial area in which only ST depression was identified. Acute myocardial infarction was defined by the presence of acute chest pain of more than 20 minutes and an elevation of creatine kinase more than twice the upper laboratory reference or creatine kinase-MB of higher than 7%. They demonstrated a sensitivity of 38% and specificity of 81% for AMI in a 12-lead multivariate ECG model vs sensitivity of 88% and specificity of 75% in a BSM model [52]. Body surface mapping might help direct upstream use of aggressive pharmacotherapy and PCI in patients deemed to have NSTEMI by ECG but who have, in fact, STEMI by BSM. If patients with nonspecific changes on 12-lead ECG can be appropriately identified as AMI by BSM, these high-risk patients might incur fewer delays to aggressive pharmacotherapy and PCI, presumably improving outcomes. This has particular relevance to emergency physicians who routinely evaluate patients with chest pain and are charged with initiating early therapy.

Body surface mapping has also displayed the potential for early detection of STEMI in specific regions of the myocardium. In particular, BSM appears to be well suited for detecting injury patterns in the RV and posterior regions associated with inferior AMI [55]. The addition of right-sided and posterior leads to conventional 12-lead ECG has been shown to enhance the anatomic description of cardiac involvement and increase sensitivity for involvement of “electrocardiographically silent” regions of the myocardium during AMI [57-62]. Menown et al [54] have shown that BSM further augments this spatial sampling, which leads to its sensitivity in detecting acute ST-segment elevation in the RV and posterior areas. Analysis of consecutive, biomarker- confirmed AMI patients with inferior ST-segment elevation revealed a greater sensitivity by regional maps when compared to 12-lead ECG enhanced by RV (V₂R, V₄R) and posterior chest leads (V₇, V₉) for identification of RV and posterior involvement. ST elevation of >=0.1 mVacross >=1 electrode on the regional RV map (BSM) was noted among 58% of subjects compared to ST elevation >=0.1 mV in selected additional RV chest leads among 42% of subjects. More notably, STelevation

>=0.1 mV in >=1 electrode was revealed in 27% of regional maps compared to STelevation >=0.1 mV shown in only 2% of subjects analyzed by additional posterior leads V₇ and V₉ [54]. The superiority of BSM over 12-lead ECG in its sensitivity for the detection of STEMI, particularly posterior AMI, has also been demonstrated by Ornato et al [53]. This multicenter trial compared BSM to 12-lead ECG in detecting STEMI among patients with biomarker-confirmed AMI and a

discharge diagnosis of AMI. PRIME showed a greater sensitivity compared to 12-lead ECG (93% vs 57% in troponin-positive AMI, P = .008) for identifying ST elevation. Specificity between the 2 diagnostic modalities was comparable (95% by PRIME, 96.5% by ECG) [53]. These findings suggest that BSM may have a role in identifying high-risk patients among AMI populations earlier and with greater accuracy. By overcoming the anatomic limitations of 12- and 15-lead ECG, rapid colorimetric body mapping generated by the 80-lead BSM system provides a larger spatial image of the myocardium, including posterior regions. This allows the clinician to identify STEMI within seconds of initial patient contact.

In addition to defining injury patterns in patients with STEMI, BSM may also improve diagnostic sensitivity for AMI in the setting of BBB. Maynard et al [56] used an 80-lead BSM device to obtain electropotential data from patients admitted to an acute medical cardiology unit with chest pain and LBBB pattern on index ECG. Of the patients with biomarker-confirmed AMI and LBBB, BSM performed with a sensitivity of 67% (specificity, 71%; positive predictive value, 52%; negative predictive value, 82%) in revealing data suggestive of AMI, whereas 12-lead ECG using Sgarbossa

criteria identified AMI with a sensitivity of 33% (specificity, 97%; positive predictive value, 86%; negative predictive value, 76%). Patients with abnormal BSM imaging in the presence of LBBB were more likely to have AMI (odds ratio, 4.9; 95% confidence interval, 1.5-6.4, P = .007). Although the sample size was small in this study (N = 56), its findings suggest a role for BSM in the detection of AMI during the evaluation of chest pain complicated by the presence of LBBB.

Body surface mapping technology: the PRIME ECG system

One example of BSM technology, the PRIME ECG System (PRIME Heartscape Technologies, Columbia, MD) uses a unique 2-piece electrode array (vest) that allows placement of 80 leads on the torso, providing a more complete view of the electrical activity of the heart. Designed primarily for ED use, this system provides analysis of the heart’s electrical activity with 360? of spatial resolution, which has the potential to detect critical diagnostic informa- tion not visible with a traditional ECG.

Fig. 3 The OCCULT-MI trial design. *The primary comparison in this study is between time to catheter laboratory (door-to-sheath time) for the patients diagnosed with STEMI by 12-lead ECG and patients diagnosed with STEMI by PRIME technology (56 ECG STEMI vs 22 OCCULT STEMI). CAD indicates coronary artery disease; DM, diabetes mellitus; HTN, hypertension; UA, unstable angina.

ST-segment elevation and depression are translated into colors (red = elevation, blue = depression) and displayed against a 3-dimensional torso image for physician review. These images allow for rapid pattern recognition to identify problem areas that correlate with regions of ischemia or infarction. This graphic imaging allows the physician to quickly focus on specific ECG morphology that contains the most valuable diagnostic information without exploring data from each of the 80 leads. The colorimetric body mapping provides the clinician with an immediate review of the ST- segment status. A sample ECG is presented in Fig. 2A, and a picture of the output using PRIME BSM technology in the same patient is shown in Fig. 2B. A coronary angiogram of the same patient is also shown (Fig. 2C).

In published studies completed over 10 years involving approximately 2500 patients, BSM has been shown to be significantly more sensitive than current Standard ECG testing in the immediate detection of such AMIs [54,63]. The earlier detection and expanded information provided by the BSM system should provide physicians with greater diagnostic insight to assess patient risk and evaluate the benefits of early intervention, a central factor in reducing adverse outcomes. Body surface mapping has been shown to have superior sensitivity over 12-lead ECG, without a significant loss of specificity, identifying ST-segment elevations outside of the 12-lead ECG purview. These STEMIs often involve RV, inferior, and posterior infarc- tions and account for approximately 22% of biomarker- confirmed acute infarctions, which are otherwise treated as NSTEMIs and recognized only after serum biomarker confirmation [51,64]. Body surface mapping diagnosis of STEMI in this setting could be the basis for more rapid access to PCI and reduced door-to-sheath time, with resultant improvements in outcomes such as cardiovascular mortality, infarct size, new-onset congestive heart failure, and subsequent hospitalizations.

The question of whether this technology is both adequately effective and user-friendly to be incorporated into standard practice has yet to be determined. A recent survey study demonstrates a lack of confidence in the 15-lead ECG. Emergency physicians were less likely to administer a fibrinolytic agent to a hypothetical patient with STEMI noted only on additional ECG leads [65]. Even with the addition of 3 leads to standard 12-lead ECG, there are regions of the myocardium that are left incompletely imaged. The substan- tially increased spatial imaging of the heart by PRIME provides a considerably more thorough imaging of the myocardium. The PRIME system may help overcome the anatomic limitations of 12- and 15-lead ECGs. This increased scrutiny of the heart may also translate into an increased rate of STEMI diagnoses, thus improving the ability to provide appropriate therapy early in the patient’s course.

This technology may result in not only faster treatment but also in a more accurate diagnosis. Physicians may easily collect and quickly analyze data from PRIME ECG in real time, even in an ED setting. There are also financial

implications of using BSM technology. It may expedite disposition in the ED and thereby improve hospital costs at presentation, prevent the need for more expensive imaging technology, reduce the incidence of rehospitalization, and ostensibly reduce the risk of malpractice for improper or delayed diagnosis.

Ongoing trial: the Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction trial

The Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT-MI) trial will measure the impact of a more complete view of the electrical signals of the heart with the PRIME ECG System, compared with the standard ECG, including time to treatment (cardiac catheterization sheath placement or door-to-sheath time) for patients diagnosed using PRIME compared with the time to treatment using the standard 12-lead ECG. The study will be an 11-site, prospective-cohort, blinded observational study of subjects presenting to the ED with symptoms of ACS. The population will consist of approximately 1400 male or female patients older than 39 years presenting to the ED with ACS symptoms of 24 hours or less, chest pain, and at least one of the following: (a) ECG abnormality; (b) known coronary artery disease; or (c) at least 3 coronary risk factors for coronary artery disease (including family history, current or treated hypertension, current or treated hypercholesterole- mia, diabetes, and current smoker).

Because the Optimal treatment of AMI depends on rapid time to reperfusion of the infarct-related artery, the primary end point of this study is door-to-sheath time. The primary objective of this study is to assess door-to-sheath time in subjects with STEMI on standard ECG and door-to-sheath time in subjects with STEMI on PRIME maps but not on standard ECG (ie, PRIME-only STEMI patients) as a measure of treatment delay that could be eliminated if the BSM system was used routinely in chest pain assessment. It is anticipated that the PRIME-only subjects will have a door-to- sheath time that is longer than those of STEMI patients.

The secondary end point of the trial is to examine the incidence of all ischemia diagnoses on BSM in subjects with nondiagnostic standard 12-lead ECGs, and the sensitivity and specificity of such findings for ACS diagnosis, as a measure of potential for enhanced triage and therapy decisions in these subjects if the BSM system was used routinely in chest pain assessment. Some of the specific key secondary comparisons in this trial will be (a) the comparison of 30-day major adverse cardiac event rates between PRIME-only STEMI patients and STEMI patients; (b) the sensitivity, specificity, positive predictive value, and negative predictive value for PRIME vs 12-lead ECG with respect to MI (adjudicated by troponin [I or T]) stratified by presence/absence of pain at time of PRIME

recording; (c) comparison of PRIME-only STEMI and STEMI subjects in terms of the distributions of coronary artery stenosis and occlusion by coronary artery location for all subjects undergoing cardiac catheterization; and (d) comparison of PRIME-only STEMIs and STEMIs in terms of the rates of revascularization (PCI or coronary artery bypass graft). The OCCULT-MI trial design is shown in Fig. 3.

Although a wealth of data support the benefit of BSM, this trial may prove the advantage of this specific PRIME technology to the degree that it should be incorporated into guidelines and quality of care initiatives in the ED.

Conclusion

The ED physician is charged with a significant respon- sibility of promptly, yet accurately, identifying ACS in patients presenting to the ED. An accurate diagnosis of STEMI or NSTEMI and subsequent appropriate therapy is hindered by many factors, including atypical presentations and suboptimal diagnostic tools. Although the 12-lead ECG is standard of care in all EDs, it has limited efficacy. The 12- lead ECG does not allow for complete imaging of the various anatomic segments of the heart and therefore fails to accurately identify a number of patients who would benefit from immediate therapy. Body surface mapping is a useful tool in the ED for assessing a patient with possible AMI. Its value lies in greater spatial representation of cardiac electrical activity than 12-lead ECG, thus allowing a more complete view of cardiac electrophysiology and greater sensitivity for detecting AMI. Body surface mapping technology affords the ED physician an excellent opportu- nity to accurately identify patients with STEMI and NSTEMI, allowing them to receive lifesaving treatment earlier in their hospital stay. This technology also allows physicians to better evaluate patients who present with chest pain but do not have AMI and avoids the unnecessary and perhaps dangerous use of thrombolysis in this group. Recent technological advances have largely overcome the previous limitations of BSM, including the need for extensive training, difficulty in interpreting the results, and cost issues. The future of BSM in the ED is not yet known but will be aided by the ongoing large-scale trial OCCULT-MI that uses the PRIME BSM technology. The potential to enhance the emergency physician’s ability to rapidly assess for AMI in difficult clinical settings and to immediately apply the appropriate therapy for STEMI or NSTEMI would result in clear benefit in care and survival.

References

1. American Heart Association. Heart disease and stroke statistics–2007 update. Dallas, TX: American Heart Association; 2007.
2. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69-e171.
3. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:671-719.
4. Fibrinolytic Therapy Trialists Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Lancet 1994;343:311-22.
5. Boersma E, Maas AC, Deckers JW, et al. Early Thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771-5.
6. De Luca G, Suryapranata H, Zijlstra F, et al. Symptom-onset-to- balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol 2003; 42:991-7.
7. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myo- cardial infarction: every minute of delay counts. Circulation 2004;109: 1223-5.
8. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-to-balloon time and Door-to-balloon time with mor- tality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941-7.
9. Stone GW, Cox D, Garcia E, et al. Normal flow (TIMI-3) before mechanical reperfusion therapy is an independent determinant of survival in acute myocardial infarction: analysis from the primary angioplasty in myocardial infarction trials. Circulation 2001;104: 636-41.
10. Cox DA, Stone GW, Grines CL, et al. Comparative early and late outcomes after primary percutaneous coronary intervention in ST-segment elevation and non-ST-segment elevation acute myocar- dial infarction (from the CADILLAC trial). Am J Cardiol 2006;98: 331-7.
11. Armstrong PW, Fu Y, Chang WC, et al. Acute coronary syndromes in the GUSTO-IIb trial: prognostic insights and impact of re- current ischemia. The GUSTO-IIb Investigators. Circulation 1998; 98:1860-8.
12. Berger PB, Ellis SG, Holmes Jr DR, et al. Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction: results from the global use of strategies to open occluded arteries in Acute Coronary Syndromes (GUSTO-IIb) trial. Circulation 1999;100:14-20.
13. McNamara RL, Wang Y, Herrin J, et al. Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2006;47:2180-6.
14. Collinson PO, Gaze DC, Morris F, et al. Comparison of biomarker strategies for rapid rule out of myocardial infarction in the emergency department using ACC/ESC diagnostic criteria. Ann Clin Biochem 2006;43:273-80.
15. Fesmire FM, Christenson RH, Fody EP, et al. Delta creatine kinase- MB outperforms myoglobin at two hours during the emergency department identification and exclusion of troponin positive non-ST- segment elevation acute coronary syndromes. Ann Emerg Med 2004; 44:12-9.
16. Rozenman Y, Gotsman MS. The earliest diagnosis of acute myocardial infarction. Annu Rev Med 1994;45:31-44.
17. Newby KH, Thompson T, Stebbins A, et al. Sustained ventricular arrhythmias in patients receiving thrombolytic therapy: incidence and outcomes, The GUSTO Investigators. Circulation 1998;98:2567-73.
18. Herring N, Paterson DJ. ECG diagnosis of acute ischaemia and infarction: past, present and future. QJM 2006;99:219-30.
19. Fesmire FM, Percy RF, Bardoner JB, et al. Usefulness of automated serial 12-lead ECG monitoring during the initial emergency depart- ment evaluation of patients with chest pain. Ann Emerg Med 1998;31: 3-11.
20. Welch RD, Zalenski RJ, Frederick PD, et al. Prognostic value of a normal or nonspecific initial electrocardiogram in acute myocardial infarction. JAMA 2001;286:1977-84.
21. Menown IB, MacKenzie G, Adgey AA. Optimizing the initial 12-lead electrocardiographic diagnosis of acute myocardial infarction. Eur Heart J 2000;21:275-83.
22. Eriksson P, Gunnarsson G, Dellborg M. Diagnosis of acute myocardial infarction in patients with chronic Left bundle-branch block. Standard 12-lead ECG compared to dynamic vectorcardiography. Scand Cardiovasc J 1999;33:17-22.
23. Brady WJ, Lentz B, Barlotta K, et al. ECG patterns confounding the ECG diagnosis of acute coronary syndrome: Left bundle branch block, right ventricular paced rhythms, and left ventricular hypertrophy. Emerg Med Clin North Am 2005;23:999-1025.
24. Gula LJ, Dick A, Massel D. Diagnosing acute myocardial infarction in the setting of left bundle branch block: prevalence and observer variability from a large community study. Coron Artery Dis 2003;14: 387-93.
25. Madias JE, Sinha A, Ashtiani R, et al. A critique of the new ST-segment criteria for the diagnosis of acute myocardial infarction in patients with left bundle-branch block. Clin Cardiol 2001;24: 652-5.
26. Sgarbossa EB, Pinski SL, Barbagelata A, et al. Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle-branch block. GUSTO-1 (Global Utilization of Streptoki- nase and Tissue Plasminogen Activator for Occluded Coronary Arteries) Investigators. N Engl J Med 1996;334:481-7.
27. Edhouse JA, Sakr M, Angus J, et al. Suspected myocardial infarction and left bundle branch block: electrocardiographic indicators of acute ischaemia. J Accid Emerg Med 1999;16:331-5.
28. Newby KH, Pisano E, Krucoff MW, et al. Incidence and clinical relevance of the occurrence of bundle-branch block in patients treated with thrombolytic therapy. Circulation 1996;94:2424-8.
29. Go AS, Barron HV, Rundle AC, et al. Bundle-branch block and in- hospital mortality in acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators. Ann Intern Med 1998;129:690-7.
30. Decker WW, Prina LD, Smars PA, et al. Continuous 12-lead electrocardiographic monitoring in an emergency department chest pain unit: an assessment of potential clinical effect. Ann Emerg Med 2003;41:342-51.
31. Hedges JR, Young GP, Henkel GF, Gibler WB, Green TR, Swanson JR. Serial ECGs are less accurate than serial CK-MB results for emergency department diagnosis of myocardial infarction. Ann Emerg Med 1992;21:1445-50.
32. Fesmire FM. A rapid protocol to identify and exclude acute myocardial infarction: continuous 12-lead ECG monitoring with 2-hour delta CK-MB. Am J Emerg Med 2000;18:698-702.
33. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990;81:1161-72.
34. Miller TD, Christian TF, Hopfenspirger MR, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation 1995;92:334-41.
35. Mak KH, Moliterno DJ, Granger CB, et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol 1997;30:171-9.
36. Stranders I, Diamant M, van Gelder RE, et al. Admission blood glucose level as risk indicator of death after myocardial infarction in

patients with and without diabetes mellitus. Arch Intern Med 2004; 164:982-8.

1. Laskey WK, Selzer F, Vlachos HA, et al. Comparison of in-hospital and one-year outcomes in patients with and without diabetes mellitus undergoing percutaneous catheter intervention (from the National Heart, Lung, and Blood Institute Dynamic Registry). Am J Cardiol 2002;90:1062-7.
2. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction-summary arti- cle: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366-74.
3. Peterson ED, Pollack Jr CV, Roe MT, et al. early use of glycoprotein IIb/IIIa inhibitors in non-ST-elevation acute myocar- dial infarction: observations from the National Registry of Myocardial Infarction 4. J Am Coll Cardiol 2003;42:45-53.
4. Hoekstra JW, Pollack Jr CV, Roe MT, et al. Improving the care of patients with non-ST-elevation acute coronary syndromes in the emergency department: the CRUSADE initiative. Acad Emerg Med 2002;9:1146-55.
5. Hoekstra JW, Roe MT, Peterson ED, et al. Early glycoprotein IIb/IIIa inhibitor use for non-ST-segment elevation acute coronary syndrome: patient selection and associated treatment patterns. Acad Emerg Med 2005;12:431-8.
6. Roe MT, Parsons LS, Pollack Jr CV, et al. Quality of care by classification of myocardial infarction: treatment patterns for ST- segment elevation vs non-ST-segment elevation myocardial infarc- tion. Arch Intern Med 2005;165:1630-6.
7. Hoenig MR, Doust JA, Aroney CN, et al. Early invasive versus conservative strategies for unstable angina & non-ST-elevation myocardial infarction in the stent era. Cochrane Database Syst Rev 2006;3:CD004815.
8. Bavry AA, Kumbhani DJ, Quiroz R, et al. Invasive therapy along with glycoprotein IIb/IIIa inhibitors and intracoronary stents improves survival in Non-ST-segment elevation acute coronary syndromes: a meta-analysis and review of the literature. Am J Cardiol 2004;93:830-5.
9. Masoudi FA, Magid DJ, Vinson DR, et al. Implications of the failure to identify high-risk electrocardiogram findings for the quality of care of patients with acute myocardial infarction: results of the Emergency Department Quality in Myocardial Infarction (EDQMI) study. Circulation 2006;114:1565-71.
10. Muller JE, Maroko PR, Braunwald E. Evaluation of precordial electrocardiographic mapping as a means of assessing changes in myocardial Ischemic injury. Circulation 1975;52:16-27.
11. Madias JE, Venkataraman K, Hodd Jr WB. Precordial ST-segment mapping 1. Clinical studies in the coronary care unit. Circulation 1975; 52:799-809.
12. Lux RL. Electrocardiographic mapping. Noninvasive electrophysio- logical cardiac imaging. Circulation 1993;87:1040-2.
13. Taccardi B. Body surface distribution of equipotential lines during atrial depolarization and ventricular repolarization. Circ Res 1966;19: 865-78.
14. McMechan SR, MacKenzie G, Allen J, et al. Body surface ECG potential maps in acute myocardial infarction. J Electrocardiol 1995; 28:184-90.
15. McClelland AJ, Owens CG, Menown IB, et al. Comparison of the 80- lead body surface map to physician and to 12-lead electrocardiogram in detection of acute myocardial infarction. Am J Cardiol 2003;92: 252-7.
16. Menown IB, Allen J, Anderson JM, et al. ST depression only on the initial 12-lead ECG: early diagnosis of acute myocardial infarction. Eur Heart J 2001;22:218-27.
17. Ornato JP, Menown IB, Riddell JW, et al. 80-lead body map detects acute ST elevation myocardial infarction missed by standard 12-lead electrocardiography. J Am Coll Cardiol 2002;39:332.
18. Menown IB, Allen J, Anderson JM, et al. Early diagnosis of right ventricular or posterior infarction associated with inferior wall left ventricular acute myocardial infarction. Am J Cardiol 2000;85(8):934-8.
19. Kornreich F, Montague TJ, Rautaharju PM. Body surface potential mapping of ST segment changes in acute myocardial infarction. Implications for ECG enrollment criteria for thrombolytic therapy. Circulation 1993;87:773-82.
20. Maynard SJ, Menown IB, Manoharan G, et al. Body surface mapping improves early diagnosis of acute myocardial infarction in patients with chest pain and left bundle branch block. Heart 2003;89:998-1002.
21. Wung SF. Discriminating between right coronary artery and circum- flex artery occlusion by using a noninvasive 18-lead electrocardio- gram. Am J Crit Care 2007;16:63-71.
22. Morris F, Brady WJ. ABC of clinical electrocardiography: acute myocardial infarction–Part I. BMJ 2002;324:831-4.
23. Khaw K, Moreyra AE, Tannenbaum AK, et al. Improved detection of posterior myocardial wall ischemia with the 15-lead electrocardio- gram. Am Heart J 1999;138:934-40.
24. Rich MW, Imburgia M, King TR, et al. Electrocardiographic diagnosis of remote posterior wall myocardial infarction using unipolar posterior lead V9. Chest 1989;96:489-93.
25. Casas RE, Marriott HJ, Glancy DL. Value of leads V7-V9 in diagnosing posterior wall acute myocardial infarction and other causes of tall R waves in V1-V2. Am J Cardiol 1997;80:508-9.
26. Zalenski RJ, Cooke D, Rydman R, et al. Assessing the diagnostic value of an ECG containing leads V4R, V8, and V9: the 15-lead ECG. Ann Emerg Med 1993;22:786-93.
27. Self WH, Mattu A, Martin M, et al. Body surface mapping in the ED evaluation of the patient with chest pain: use of the 80-lead electrocardiogram system. Am J Emerg Med 2006;24:87-112.
28. Owens CG, McClelland AJ, Walsh SJ, et al. Prehospital 80-LAD mapping: does it add significantly to the diagnosis of acute coronary syndromes? J Electrocardiol 2004;37(Suppl):223-32.
29. Brady WJ, Hwang V, Sullivan R, et al. A comparison of 12- and 15-lead ECGS in ED chest pain patients: impact on diagnosis, therapy, and disposition. Am J Emerg Med 2000;18:239-43.