Since the introduction of string galvanometer by Dutch physiologist Willem Eithoven in 1902, electrocardiography has undergone significant technical advances. Digital recording methods and computer-based signal processing, storage, and analysis allow clinicians and researchers to detect clinically significant electrocardiographic changes in small magnitude.

The electrocardiogram (ECG) is easily available, noninvasive, inexpensive, and reproducible; thus, it has become the most commonly used technical procedure for the evaluation of cardiovascular structure and function in health and disease.1 Because the ECG reflects electrophysiologic, anatomic, metabolic, and hemodynamic alterations, it is routinely used for the diagnosis of myocardial ischemia, cardiac arrhythmias, structural changes of the myocardium, drug effects, and electrolyte and metabolic disturbances.2 As a research tool, the ECG is used in various capacities, including long-term population-based surveillance and monitoring of recognized or potential cardiac effects in experimental drug trials.1

Because of the broad applicability of the ECG and extensive literature on this subject, it is impossible to discuss all electrocardiographic parameters for the evaluation of cardiovascular status. Recent work on the utility and effectiveness of specific ECG changes for identifying patients at risk of life-threatening ventricular arrhythmias has shown evidence of promising results. Therefore, the purpose of this paper is focused on recent work that used ECG, specifically the long-QT interval and microvolt T wave alternans (MTWA), for the evaluation of ventricular arrhythmias.

Long-QT Interval and Torsade de Pointes

QT prolongation has attracted a great deal of attention in recent years because of its association with malignant polymorphic ventricular tachyarrhythmia, torsade de pointes (TdP), which can occasionally degenerate into ventricular fibrillation, leading to sudden cardiac death. Long-QT interval may be due to any of several congenital disorders such as familial long-QT syndrome (LQTS) or an acquired LQTS caused by drugs and several clinical conditions.3-5 These cardiac and noncardiac conditions that can prolong the QT interval include but are not limited to myocardial ischemia, congestive heart failure, myocarditis, mitral valve prolapse, bradyarrhythmias, electrolyte abnormalities, and female gender. However, the most common factor resulting in acquired LQTS is drug therapy. Recently, significant effort has been focused on the identification of drug-induced QT prolongation with the goal of preventing fatal arrhythmias.

The QT interval on the surface ECG is measured from the beginning of the QRS complex to the end of the T wave. This interval reflects the time at the beginning of ventricular depolarization up to the completion of ventricular repolarization. The QT interval is dependent on the heart rate-the higher the heart rate, the shorter the QT interval, and vice versa. Several formulas are available to correct the QT interval (QTc) based on heart rate, such as the Fridericia,6 Framingham linear regression,7 and Bazett8 (Table 1). Although the Bazett formula has been criticized for undercorrecting QT interval at low heart rates and overcorrecting at high heart rates,9,10 it is most often being used clinically due to its simplicity. Although these formulas are appropriate for diagnosing familial LQTS, their use in evaluating drug-induced QT changes may lead to either false-positive or false-negative findings.11,12 When a drug-induced heart rate changes and thus alters the R-R interval, it is important to distinguish a QT change that is due to a drug effect versus an artifact of a heart rate change. In addition, it has been questioned that a generic QT correction equation for all patients may be inadequate because a formula that is accurate for one patient may be inaccurate when applied to another individual.12 Therefore, Malik12 suggested the use of each individual's baseline data to generate a subject-specific QT correction formula so that the true QT prolongation is derived from the actual drug effect and not as an artifact from rate correction formulas. Optimal formulas correcting the QT interval for heart rate, which are either universally applicable or individualized in predicting which patients are at greatest risk for TdP, remain to be validated.

TABLE 1 QT Correction Formulas

Two electrophysiologic mechanisms underlying TdP have been summarized by Tamargo.13 In brief, one hypothesis proposed that prolongation of the QT interval and TdP is caused by early after-depolarizations, which is defined as single or repetitive depolarizations occurring during phase 2 or 3 of the action potential that delay repolarization.14 Early after-depolarizations can initiate a premature action potential or a train of action potentials and are considered a potential initiating mechanism for the arrhythmia. A second hypothesis states that increased heterogeneity of repolarization across cell types within ventricular myocardium lowered the ventricular arrhythmic threshold. Ventricular myocardium contains at least 3 types of cells, epicardial, endocardial, and midmyocardial cells, each with action potentials that differ in morphology and duration. The action potential in each cell type responds differently to pharmacologic agents and changes in heart rate. This difference across the ventricular wall is physiologic but, if exaggerated, has been associated with risk for TdP. 15

In 1978, Schwartz and Wolf16 reported an increase in the incidence of sudden death by more than 2-fold in patients with a myocardial infarction (MI) when the QTc using the Bazett formula was prolonged to 440 milliseconds. In 328 families with LQTS, Moss and colleagues17 found that a QTc threshold value of 500 milliseconds demarcated familial LQTS patients with higher and lower risk for ventricular tachyarrhythmic syncope and sudden death. In 1981, Keren et al18 also showed that a QT prolongation of greater than 600 milliseconds (or QTc > 520 milliseconds) was found in all patients who developed drug-induced TdP. However, some studies also revealed that many patients developed TdP with little or no QT prolongation.3,19 Although there is no established threshold as to what is considered a "good" and "bad" QT prolongation, a consensus exists that a QTc interval greater than 500 milliseconds is of concern.20

Although prolonged QT interval can be arrhythmogenic and lead to TdP, recent studies demonstrated that QT prolongation alone appears insufficient to cause arrhythmias.21,22 For example, the primary mechanism underlying the therapeutic effect of Class III antiarrhythmic agents is to prolong repolarization in all 3 cell types, which usually results in significant QT prolongation but reduces the transmural dispersion, diminishing the likelihood of TdP. Therefore, measuring the QT interval alone may not be an accurate guide to TdP risk. Instead, other indices of repolarization, such as T wave morphology, T peak-to-T end time, or beat-to-beat QT variability (changes in QT duration on alternating beats), have been proposed to be more sensitive indicators of TdP.21,23-25 For example, in an animal study, the interval from the peak to the end of the T wave on the ECG correlates with transmural dispersion of repolarization,26 suggesting it to be a more specific ECG indicator of TdP risk in the setting of a long-QT interval. This finding was supported in a cohort of patients with drug-induced LQTS who developed TdP.27

Microvolt T Wave Alternans

T wave alternans (TWA) is defined as variation in the morphology and amplitude of the T wave on an every other beat basis.28 Visible "macroscopic" TWA was first reported by Herring in 1909 and, even with very low incidence, has subsequently been associated with a high risk of ventricular tachyarrhythmias in patients with familial LQTS29 and acute coronary ischemia.30-32 With the development of new computer-processing techniques, TWA on the order of a few microvolts, termed MTWA, can be detected.33 Rosenbaum et al34 published the first prospective human study demonstrating a strong relationship between MTWA and the vulnerability to ventricular arrhythmias in the electrophysiology laboratory, as well as spontaneous ventricular tachyarrhythmias during follow-up.

The majority of evidence favors that TWA is caused primarily by beat-to-beat heterogeneity of repolarization. Using an animal preparation, Shimizu and Antzelevitch35 found that MTWA was due to beat-to-beat alternation of midmyocardial cell action potential duration compared with epicardial or endocardial cells. Arrhythmogenic mechanisms associated with T wave alternans have also been hypothesized elsewhere.28,36,37

The MTWA assessment method is described in detail by Rosenbaum et al.38 In brief, MTWA is not generally present at rest even in patients at risk of ventricular tachyarrhythmias, and therefore, a noninvasive exercise test or invasive atrial pacing is used to increase the heart rate. Results of a recent study suggested that the accuracy of invasive MTWA assessment may be inferior to the noninvasive approach.39 Sequential ECG cycles are recorded and aligned to their QRS complexes, and the T wave amplitudes at a predefined point are measured. Computer algorithms are used to detect and quantify this beat-to-beat series of amplitude fluctuations, and the most widely applied technique is the spectral analysis using fast Fourier transformation.40 Microvolt T wave alternans recordings can be classified as positive, negative, or indeterminate (Table 2).

TABLE 2 Classifications of Microvolt T Wave Alternans Test Results

Analysis of MTWA has received enormous interest and emerged as the most promising noninvasive detection of patients prone to ventricular tachyarrhythmias and sudden cardiac death. Considerable work has linked MTWA to the genesis of life-threatening ventricular tachyarrhythmias.41 Evidence from these trials indicates that noninvasive assessment of MTWA is an important tool for determining the risk for ventricular tachyarrhythmic events in broad patient populations, including those with ischemic and nonischemic heart disease.42 Investigators have also demonstrated that MTWA can predict total mortality in patients with ischemic heart disease and left ventricular dysfunction without prior history of arrhythmia.43,44

More recently, a number of studies have examined the clinical applicability of MTWA in patients with ischemic cardiomyopathy, particularly those fulfilling the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) criteria. The MADIT II study was conducted to evaluate the potential survival benefit of a prophylactic implantable cardioverter defibrillator (ICD) in patients with a prior MI and severe left ventricular dysfunction (ejection fraction < 30%).45 These researchers found that as compared to conventional medical therapy, ICD therapy was associated with a 31% reduction in the risk of death. Although ICD is a life-saving therapy in preventing sudden arrhythmic death in this population, these devices incur a significant health-cost burden. In addition, the available stratification does not permit a high specificity in selecting patients at high risk of life-threatening arrhythmias. Cost efficacy calculations predict that over 3 years, roughly between 11 and 17 ICDs were used to save 1 life. This suggests that a more accurate identification of high-risk patients is needed to avoid unnecessary ICD implantation.45,46 Therefore, recent work has been focused on risk stratification with MTWA to noninvasively identify patients who are most and least likely to benefit from prophylactic ICD therapy.

In a retrospective analysis47 selecting MADIT II type patients from prospectively studied cohorts,48,49 it was demonstrated for the first time that a negative MTWA test can identify patients who may not benefit from prophylactic ICD placement. This evidence is further substantiated by several larger prospective studies.43,50,51 For example, Chow et al43 studied 768 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fraction <= 35%) and without prior history of ventricular tachyarrhythmic events and reported that a nonnegative test (positive or indeterminate) found in 67% of the patients was associated with a higher risk of all-cause and arrhythmic mortality. Recently, the same investigators further assessed whether ICD placements have different mortality benefits among patients with ischemic cardiomyopathy who screen negative and nonnegative (positive and indeterminate) MTWA.51 They found that ICD therapy was associated with significantly lower all-cause mortality in MTWA-nonnegative patients but not in MTWA-negative patients. The results also indicated that the number of patients needed for years of treatment with an ICD to save 1 life would be 9 among MTWA-nonnegative patients and 76 among MTWA-negative patients. Therefore, findings from these studies suggest that MTWA may effectively risk-stratify patients with ischemic cardiomyopathy by identifying subgroups who receive substantial versus minimal benefit from ICD therapy.

Similar findings were reported in a prospective multicenter study that included 549 patients with left ventricular dysfunction.52 Half of this patient population had ischemic cardiomyopathy and underwent MTWA assessment. During a follow-up period of 20 +/- 6 months, the all-cause mortality and sustained ventricular arrhythmias rate was 15% in the MTWA-nonnegative group versus 2.5% in the MTWA-negative group. Data from this study suggested that MTWA testing can identify a low-risk group with left ventricular dysfunction which has an excellent prognosis and is unlikely to benefit from prophylactic ICD therapy.

Most recently, Cantillon et al53 extended our knowledge in the use of MTWA in 286 patients with left ventricular dysfunction and additional risk profiles, including syncope or nonsustained ventricular tachycardia. They evaluated 286 patients who underwent MTWA and electrophysiologic testing and found that MTWA-negative patients had improved 2-year arrhythmia-free survival compared with MTWA-nonnegative patients (81% vs 66%, P < .0001). The high event rate in the MTWA-negative group suggests that MTWA may not be sufficient in identifying a low-risk subset to obviate the need for prophylactic ICD implantation in this population.

Currently available data in patients with left ventricular dysfunction suggest that the predictive efficacy of MTWA test is largely dependent on the population studied. The underlying pathology of left ventricular dysfunction and the presence or absence of additional clinical risk factors may affect the pretest probability of a ventricular tachyarrhythmic event.54 In patients fulfilling MADIT II criteria, evidence suggests that a negative MTWA identifies a subset of patients at a low risk of ventricular tachyarrhythmic events. Recommendations on the use of MTWA should be based on future interventional trials in well-defined patient populations. Timing and frequency to screen patients with MTWA testing have yet to be determined.

Some controversy remains regarding MTWA testing in early post-MI risk stratification. Forthcoming results from 2 recently completed studies, the Microvolt T Wave Alternans Testing for Risk Stratification of Post-MI Patients and the Risk Estimation Following Infarction-Noninvasive Evaluation trials, may help to define the role of MTWA in predicting life-threatening ventricular arrhythmias and survival in patients after MI. The Microvolt T Wave Alternans Testing for Risk Stratification of Post-MI Patients trial (http://clinicaltrials.gov/ct/show/NCT00305240) investigated the role of MTWA in predicting ventricular tachyarrhythmic events in 650 post-MI patients with reduced left ventricular function who were indicated for primary prophylactic ICDs. The Risk Estimation Following Infarction-Noninvasive Evaluation study (http://clinicaltrials.gov/ct/show/NCT00399503?order=1) evaluated the role of MTWA testing in arrhythmogenic risk stratification of 350 recent MI patients with a left ventricular ejection fraction less than 50%.

In summary, accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical for the development of effective strategies to prevent sudden cardiac death. Electrocardiography is the most commonly conducted cardiovascular diagnostic procedure and may provide valuable information for noninvasive risk prediction. Nurse clinicians and advanced practice nurses are at the forefront in monitoring and interpreting cardiac arrhythmias as well as dispensing, prescribing, and educating patients about QT-prolonging medications. Therefore, it is imperative that nurse clinicians/practitioners understand the current state of science, can recognize patients at risk for acquired LQTS and ventricular arrhythmias, and use rigorous assessment strategies to prevent the deleterious consequences of sudden cardiac death. Although remaining to be validated, QT prolongation, MTWA, along with other emerging electrocardiographic indices have received enormous interest and may be promising noninvasive markers for the identification of patients prone to ventricular tachyarrhythmias and sudden cardiac death. These ECG markers have the potential to aid in the safe administration of individualized medications, avoidance of sudden cardiac death, and provision a noninvasive strategy to identify patients who are most and least likely to benefit from expensive prophylactic ICD placement.

Acknowledgments

Dr Wung's work has been supported in part by grants from the National Institute of Nursing Research (RO1 NR008092 and P20NR007794), Sigma Theta Tau International, American Association of Critical Care Nurses, Emergency Nurses Association, and Laurence B. Emmons Award, College of Nursing, The University of Arizona.

REFERENCES