A أسلوب البحث العلمي للكشف عن نقص تروية عضلة القلب في المرضى الذين يعانون عابر متلازمة الشريان التاجي الحادة عن طريق يشتبه المستمر ST-الجزء تحليل

According to the most recent American Heart Association statistics, coronary artery disease (CAD) was estimated to be responsible for 1.2 million hospital stays and was the most expensive medical condition treated.¹ More than half of the hospital stays for CAD were among patients who also received percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) during their stay. Because of the prevalence of CAD, clinicians working in hospitals are likely to encounter these patients frequently. The purpose of this manuscript is to describe the ECG application and analysis methodology used in the COMPARE Study (electroCardiographic evaluatiOn of ischeMia comParing invAsive to phaRmacological trEatment; (R21 NR-011202), which might be utilized by other researches exploring this clinical problem.

Each year, nearly 700,000 Americans will have a new coronary attack, or acute coronary syndrome (ACS).¹ The pathophysiology of ACS involves rupture of an atherosclerotic plaque; hence, treatment is aimed at plaque stabilization in order to prevent cellular death. However, there is considerable debate among clinicians, about which treatment pathway is best: early invasive using percutaneous coronary intervention (PCI/stent) when indicated or a conservative approach (i.e., medications only or PCI/stent if recurrent symptoms occur).^2-5

There are three types of ACS: ST elevation myocardial infarction (STEMI), non-ST elevation MI (NSTEMI), and unstable angina (UA).⁶ Among the three types, NSTEMI/UA is nearly four times as common as STEMI.^7,8 Treatment decisions for NSTEMI/UA are based largely on symptoms and resting or exercise electrocardiograms (ECG). However, because of the dynamic and unpredictable nature of the atherosclerotic plaque, these methods often under-detect myocardial ischemia because symptoms are unreliable, and/or continuous ECG monitoring was not utilized.

The manifestations of NSTEMI/UA may include (1) symptoms (chest, arm, jaw or neck pain, sweating, nausea), (2) release of cardiac biomarkers in the case of NSTEMI (Troponin I, Troponin T, or creatnine kinase-MB) and (3) electrocardiographic (ECG) changes (intermittent ST elevation/depression, or T-wave inversion). While symptoms may occur in ACS, it is well documented that transient episodes of ECG-detected ischemia are clinically silent in over 70% of patients.^9-12 Importantly, many studies have found that patients with ECG-detected ischemia, as compared to patients without such events, were at higher risk for unfavorable outcomes in both the short term^11-13 and long term.^14-16 Hence, symptoms are an unreliable indicator of ischemia in NSTEMI/UA, which is problematic since treatment decisions for an early invasive strategy or initial medication strategy are often driven by patient symptoms.^2-5 Further, biomarkers identify NSTEMI/UA patients too late because their presence in the serum indicates that cellular death has already occurred.

Electrocardiographic changes indicative of ischemia occur within seconds of diminished coronary blood flow.^10,17 The portion of the ECG complex that changes during acute ischemia is the ST-segment, which is measured at one of three points; (1) J-point, (2) J point plus 60 milliseconds (msec) or, (3) J-point plus 80 (msec) (Figure 1).

The 12-lead ECG has important advantages over both symptoms and biomarkers in identifying MI in that it is non-invasive, inexpensive, and if maintained continuously can identify transient ischemia, even when it is clinically silent. While 12-lead ECG monitoring is ideal because multiple areas of the heart are assessed, typical hospital practice incorporates monitoring with only two ECG leads. The two ECG leads most commonly monitored by nurses in the hospital setting are leads V1 and II.¹⁸ Unfortunately, these two leads are not sensitive for detecting transient ischemia in many ACS patients.^10,19 Therefore, ischemia occurring outside of these two monitored leads will be missed.

Using 12-lead ECG monitoring the COMPARE Study is designed to assess the frequency and clinical consequences of transient myocardial ischemia, in patients with NSTEMI/UA treated with early invasive PCI/stent compared to those managed with an initial conservative approach, which includes medications alone, with transition to PCI/stent following recurrent symptoms. In our study, continuous 12-lead ECG Holter recorder is used to capture ischemia. The aim of this descriptive study is to assess the frequency and clinical consequences of transient myocardial ischemia, in patients with NSTEMI/UA treated with either early invasive PCI/stent or those managed conservatively (medications or PCI/stent following recurrent symptoms).

Methodological Challenges

While computer-assisted ST-segment software works well for detecting transient ischemia, accurate analysis requires careful, expert human oversight. Important factors to consider during analysis include (1) artifact, (2) the consistency and accuracy electrode placement, (3) body position changes, (4) drug effects, and (5) sudden waveform changes.²⁰ Each of these factors will be discussed below.

Artifact: Because clinically significant ST-segment changes are as small as 100 microvolt (one small box on the ECG paper), noisy signal from muscle artifact can significantly hinder analysis. Most artifacts are related to improper skin preparation.²¹ The problem can be easily solved with careful skin preparation of the patient’s torso at the outset of monitoring and as needed throughout the monitoring period.^21-23 Skin preparation should include removal of hair at the sites of electrodes, vigorous removal of skin oil/debris, and use of an alcohol prep pad and/or a washcloth.^23,24

Consistency and Accuracy of Electrode Placement: False positive ST-segment changes can occur when electrodes are moved or removed during monitoring.²⁰ This can be managed by marking each electrode site with indelible ink at the outset of monitoring to ensure that electrodes are reapplied to the correct location if they fall off or are removed for procedures (e.g., echocardiogram, X-rays).²⁵ We recommend an assessment of the patient’s torso at least every 4 hr to ensure skin electrodes are on the chest.

Body Position Changes: Studies using continuous ST-segment monitoring have shown that some patients can exhibit concomitant QRS and ST-segment amplitude changes during body position changes (i.e., left-, or right-side lying), which can be mistaken for myocardial ischemia.^26,27 Our research team found that body position changes were the most common cause of false positive ST-segment alarms.²⁰ Using echocardiography, Feldman and co-workers²⁸ found that when patients moved from a supine to a left side-lying position, the left ventricle moved closer to the lateral chest wall. This had a direct effect on the distance of the left ventricle from the chest electrodes and resulted in an increase in the amplitude of the R-wave in the ECG leads over this myocardial territory. These changes have been confirmed by others.^26,27 In general, positional ECG changes are suspected when ECG waveform amplitudes increase with concomitant ST-segment changes. A helpful strategy is to obtain ‘positional template ECGs’ with patients assuming supine, left- and right-side lying positions when monitoring is initiated, for later comparison during the analysis.

Pharmacological Effects: Even in therapeutic doses drugs can affect ECG waveforms. Drugs that alter the ST-segment are particularly important since they lead to a misdiagnosis of myocardial ischemia.²⁹ These drugs include digitalis, antiarrhythmics, and phenothiazines. The “digitalis effect” is used to describe the characteristic ST-segment and T wave changes that can occur with this drug, including ‘coved’ ST-segment depression, a flattened T-wave and a short QTc interval.³⁰ Other drugs, such as the antiarrhythmics (i.e., quinidine, sotalol and amiodarone)³⁰ and phenothiazine, used to treat schizophrenia/psychotic disorders, increase the QTc interval, and decrease T-wave amplitude.³¹

Nevertheless, patients taking these drugs can be monitored for acute ST-segment changes that may indicate acute myocardial ischemia. The baseline abnormalities seen with the drugs are chronic; hence any ST-segment deviation (depression or elevation) that occurs from the patient’s baseline ST-segment level should be assessed for acute ischemia.

Sudden Waveform Changes: Transient conditions, such as arrhythmias, right- or left bundle branch block (BBB), and intermittent ventricular paced beats, can distort the ST-segment and lead to a false-positive ischemia diagnosis.²⁰

In summary, continuous ST-segment monitoring is an excellent tool for identifying transient myocardial ischemia in patients with suspected ACS. However, this method requires that careful application of electrodes and leads wires is performed at the initiation and throughout monitoring. This method also requires careful human oversight in order to eliminate false positive ST-segment changes.

Step-by-Step Methodology

In the COMPARE study, a digital Holter recorder is used (H12+, Mortara Instruments, Milwaukee, WI), which records electrical potentials sampled at 4-msec intervals over a 10-sec period to identify a median beat. All 12 ECG leads (I, II, III, aVR, aVL, aVF, V1-V6) are simultaneously acquired at a digital sampling rate of 1,000 samples per sec per channel which is stored to a compact flash memory card. In addition, the H12+ features electrode impedance measurement to ensure proper skin preparation prior to beginning the Holter recording. A display indicates if an ECG lead has become detached and also provides an internal clock for recording of diary events. Data from the Holter monitor flashcard is then downloaded to the H-Scribe, an off-line Holter Analysis System (Mortara Instruments, Milwaukee, WI). The software allows analysis of continuous ECG recordings to determine the quality of the signal, presence of arrhythmias, and ischemia.

Research assistants with experience working with the cardiac patient population collect the ECG Holter data. A training session at the start of the study was scheduled to ensure the quality and consistency of the study protocol. A training session covering the ECG monitoring procedure, including how to apply ECG monitoring equipment, initiate/maintain ECG monitoring, and download ECG Holter data onto the research computer was done. Return demonstrations were performed and inter-rater reliability is done throughout the study by randomly assessing 10% of currently enrolled subjects. Bi-weekly research team meetings ensure that recruitment goals are being met, challenges are discussed, and results of inter-rater reliability tests can be shared.

The research methodology used in the COMPARE Study has two important steps; patient preparation and off-line ECG analysis. Both of these methods will be explained in a step-by-step manner in the subsequent section.