The electrocardiography (ECG) is pivotal in evaluating patients with suspected coronary artery disease (CAD). However, in patients who present to the emergency department (ED) with a chief complaint of chest pain, the initial ECG may be normal despite later discovery of CAD (Fig. 1). The rate at which this phenomenon occurs (3% to 16%) varies widely in the literature [1,2].

Patients who present to the ED with chest pain and with normal or nonspecific ECG interpretations have low rates of mortality and cardiac complications [3] and thus are considered low-risk [4]. Nevertheless, a normal or nonspecific ECG tracing does not exempt a patient from risk for cardiovascular events. Normal ECGs may contribute to increased mortality in patients who present to the ED who consequently are not hospitalized for acute cardiac ischemia [5]. There is also the possibility that changes consistent with myocardial ischemia may develop later, despite initial ECG tracings that are normal [6]. In one large study of patients with initially normal or nonspecific ECGs, respective hospital mortality rates of 5.7% and 8.7% were recorded [7].

To date, no algorithm exists to reliably predict adverse cardiovascular outcomes in patients with potential CAD based on a normal ECG alone (i.e., in the absence of ischemic changes) [8] or in conjunction with cardiac markers [9] or a history of angina [10]. Emergency echocardiography is a promising diagnostic tool, but it too has limitations. For example, regional wall motion abnormality (RWMA) was found in 22% of patients without CAD, and 12% of patients with CAD showed no evidence of RWMA [11].

In patients with normal or nonspecific ECGs, a means of differentiating those with and without CAD is clearly needed. The objective of our study was to determine the incidence of CAD in patients with normal or nonspecific ECGs, evaluating specific ECG features and other clinical parameters that are potentially predictive of CAD in this context.

The ECG is a valid means of risk stratification for patients who present on an emergency basis with chest pain or discomfort. Studies indicate that low-risk patients with chest pain may be identified upon presentation at the ED by clinical evaluation plus ECG [14], and those patients with normal ECGs are considered low-risk [15,16]. However, clinically significant (albeit lower) short-term mortality rates have been recorded in patients with CAD and normal or nonspecific ECG tracings, compared with similar patients whose ECGs are abnormal [7], and a normal ECG has been cited as a significant factor in the failure to diagnose acute MI at emergency facilities [5]. Thus, the broad generalization that normal ECGs are low-risk may limit detection of ischemia in the following circumstances: (1) occlusive lesions of the LCX [17]; (2) prior acute MI; (3) established CAD [18]; (4) adequate collateral coronary circulation [19]; (5) transiently normal ECG [20]; and (6) small infarctions [17,21].

Our study illustrates that in patients with CAD, those with normal or nonspecific ECGs had a higher frequency of lesions involving the LCX. Chua et al. [17] similarly demonstrated that LCX-related acute MI that presented without ST-T changes has been underdiagnosed in ED settings, with ST-T changes absent in 23% of patients who were suffering LCX occlusion. In contrast, Caceres et al. [2] found that the frequency of LCX involvement in patients did not differ by ECG status (normal vs. abnormal).

Notching of QRS complexes has been the subject of much discussion in many recent studies. It is commonly upheld that fQRS correlates with an array of disorders, including CAD, dilated cardiomyopathy, cardiac sarcoidosis, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, and long QT syndrome, as shown by myocardial perfusion-gated SPECT (single photon emission computed tomography) studies, CAG, and late gadolinium-enhanced cardiac magnetic resonance imaging [22-24]. In addition, fQRS has been identified as an independent prognosticator of mortality or cardiac events [25] in the setting of MI [23,26], with some evidence that equates the number of leads affected with the severity of the coronary lesions [27,28]. As demonstrated by Boineau [29], multiple MIs may lead to ECG modifications, with loss of Q waves and development of M- or W-shaped QRS complexes (fQRS). Other recent studies have shown that fQRS correlates poorly with myocardial scarring and is instead related to functional or anatomical ventricular abnormalities [30-32].

According to Lee and Goldman [33] the CK-MB level at the early onset of chest pain is a more accurate and sensitive index of MI than troponin I or troponin T. Wang et al. [21] discovered that among patients who presented with non-ST-segment elevation acute coronary syndromes, higher CK-MB (p < 0.0001) and troponin I (p = 0.001) levels corresponded with coronary arterial occlusion, which was documented by CAG in 27% (528/1,957) of their subjects.

We contend that male sex, abnormal CK-MB, and fQRS can be used as important diagnostic tools to predict coronary occlusion in patients with suspected CAD and normal ECGs. The association between CAD and a number of predictors (male, p = 0.696; fQRS, p = 0.053) in multivariable analysis was more decreased than that found in the univariable analysis. The reason the p value was higher than 0.05 in the multivariable analysis was the small sample size; better results will be shown through large multicenter studies. Herein, we evaluated fQRS complexes in normal patients without CAD, whereas most prior studies of fQRS have looked at high-risk diseases such as MI or cardiomyopathy; few researchers have focused on the significance of fQRS complexes in the general population.

Although a number of variables in our collected data generated statistically negative outcomes, the significance of these variables is still debatable. A Q wave is generally abnormal if its duration is 0.04 seconds or longer in lead I, in all three inferior leads (II, III, aVF), or in leads V3 through V6 [34], and a pathologic Q wave is one involving two or more contiguous leads. The presence of a Q wave in the aftermath of MI is associated with higher in-hospital morbidity and mortality [35]. Furthermore, a history of prior MI in patients with non-ST-elevation CAD poses a significant risk [21]. Some sources have shown that prolonged corrected QT intervals are predictive of cardiac events after MI [36]. Elsewhere, however, pathologic Q waves, corrected QT intervals, and previous ischemic heart disease were unrelated to prognosis (i.e., major adverse cardiac events) [37]. Still, one publication does maintain that fQRS complexes are superior to pathologic Q waves in terms of their sensitivity to and negative predictive value for myocardial scarring [38]. We similarly contend that fQRS is a superior index of CAD to pathologic Q waves or history of prior MI.

In our hands, RWMA detected by emergency echocardiography (done prior to CAG and performed by a cardiologist or sonographer) curiously showed no statistical association with significant stenotic lesions of a coronary artery. Possible explanations are as follows: (1) latent stress-related cardiomyopathy, such as isolated basal LV dysfunction, global LV hypokinesia, and other wall motion abnormalities in non-coronary distribution (aside from Takotsubo cardiomyopathy) [39], in patients with angina and normal ECGs; (2) residual RWMA as from previous MI; (3) RWMA undetected because of minute or diffuse multiple coronary lesions; (4) execution error by untrained cardiologists or sonographers; and (5) paucity of suitable cases.

This study has a number of acknowledged limitations, one being the limited (for statistical purposes) number of patients with normal ECGs who were admitted for angina through our emergency services. Another is the retrospective nature of the study and its restriction to a single institution. Nevertheless, nearly all required data were collected successfully with the exception of some laboratory results. Finally, collateral coronary arterial circulation was not investigated owing to the incompleteness of our records, and patients (with potential CAD) who did not undergo CAG were excluded from study.

In conclusion, our data indicate that male sex, CK-MB levels beyond a set threshold, and fQRS complexes on ECG are predictive of CAD in patients with angina and normal ECGs. The presence of fQRS on ECG and elevated CK-MB in this context also appear to reflect coronary arterial stenosis in 70% or more of cases. These findings clearly merit further study.