Rates of sudden cardiac death due to heart rhythm abnormalities remain at high levels despite significant advances in technology and therapy of patients with coronary artery disease. Sudden deaths account for more than three-quarters of coronary artery disease deaths, totaling 310,000 per year in the U.S. More than half of the individuals who died suddenly had no warning signs. While risk for sudden death is increased four- to six-fold in patients who have experienced myocardial infarction, it remains challenging to identify the specific patients who will benefit from the standard-of-care therapy, namely, implantation of an implantable cardioverter defibrillator (ICD).
Mechanical function of the heart, as measured by left ventricular ejection fraction, is the only indication that is currently reimbursed for ICD implantation. But it is inaccurate, since based on this marker only one in eight patients who receive an ICD ever have it fire to rescue the patient from the lethal heart rhythm. Moreover, most sudden deaths occur among individuals whose mechanical function is normal or only marginally abnormal. Clearly, there is a great need for a more precise indicator of sudden death risk, particularly one that can be used in patients with preserved mechanical function, to allow cardiologists to target preventive strategies more precisely.
T-wave alternans (TWA), an alternation in the size and shape of the T-wave in the electrocardiogram (Figure 1), can serve as a warning signal and index of risk for sudden death. A consensus guideline statement on TWA, co-authored by 11 international experts and published in the September issue of Journal of the American College of Cardiology, reviewed the prospective clinical studies on TWA that have been published in the peer-reviewed medical literature. These investigations enrolled more than 12,000 patients and reported that patients with high levels of TWA carry a 2.5- to 23-fold increased risk of sudden death over patients with lower TWA values. The studies were conducted in a number of patient groups, including those with an indication for stress testing, coronary artery disease, acute or prior myocardial infarction, history of arrhythmia, ischemic or dilated cardiomyopathy or heart failure, as well as those with congenital heart disease. The consensus guideline authors concluded that TWA provides information on risk of death from coronary artery disease beyond mechanical function (the conventional marker for ICD implantation) and beyond traditional risk markers such as smoking, blood pressure and cardiac history.
The report discussed two analytical methods for TWA in depth. The traditional spectral method requires proprietary single-use electrodes and a specialized exercise protocol to raise the patient’s heart rate. It must be scheduled as a separate test and cannot be used in patients who cannot undergo the specialized stress protocol. It reports results as “positive,” “negative” or “indeterminate.”
By contrast, “modified moving average” (MMA) analysis allows cardiologists to scan routine electrocardiograms (ECGs) from ambulatory recordings and standard symptom-limited exercise stress tests to identify the presence and measure the size of TWA, even when it is not readily visible. This type of TWA analysis can be conducted in the flow of routine clinical evaluation. It measures TWA with the same 1-microvolt resolution as the spectral method and was found by the consensus guideline authors to be equivalent to that method in its capacity to predict sudden death.
MMA analysis was employed in the largest prospective clinical study on TWA published to date, the Finnish Cardiovascular Study (FINCAVAS), which enrolled nearly 3,600 patients referred for routine, symptom-limited exercise stress testing. The investigation verified that MMA-based TWA identified patients whose risk for sudden death is significantly elevated. In most of the FINCAVAS patients, cardiac mechanical function was preserved, and the results indicate that MMA is feasible for use in screening the large population in which the majority of sudden deaths occur. The MMA algorithm was developed by Drs. Verrier and Nearing, Harvard Medical School faculty members at Beth Israel Deaconess Medical Center, and is an integrated module in GE Healthcare ambulatory ECG and exercise stress testing equipment.
While many TWA studies have addressed the need to identify patients who would — or would not — benefit from ICD implantation, TWA testing can also be used to guide medical therapy. As a practicing cardiologist, I use the MMA method to analyze the ECGs of many of my patients. I have found that the TWA measurements provide me with important information for adjusting their medications – in particular, beta-blocking agents, which are known to decrease risk for sudden death. These agents also lower the peak MMA level, reflecting their anti-sudden death efficacy.
The larger the TWA signal, the greater the risk for sudden death. If I can lower a patient’s TWA level to less than 40 microvolts, I have confidence that the patient is benefitted, since for every 20-microvolt reduction in TWA there is a greater than 50 percent decrease in sudden death risk. In addition, the MMA report displays a trend of TWA levels in the patient’s ECG. The template tool (Figure 1), a unique feature of GE Healthcare’s TWA analysis software, allows me to inspect the particular segments of the ECG with reported high levels of TWA. While there are many guidelines for optimizing medical therapy, no marker other than TWA specifically monitors vulnerability to ventricular arrhythmias. Using this tool in conjunction with my overall clinical assessment of the patient’s risk increases my confidence in prescribing medications. You might say that I use TWA as a “therapeutic target.”
I thoroughly agree with the consensus guideline authors, who concluded, “It is reasonable to consider TWA evaluation whenever there is suspicion of vulnerability to lethal cardiac arrhythmias,” concurring with recommendations of guidelines committees of the American Heart Association, the American College of Cardiology, the European Society of Cardiology and the Heart Rhythm Society.
Editor’s note: David Ancona, M.D., FACC, is a practicing cardiologist at Memorial Hospital West in Pembroke Pines, Fla.
1. “Heart Disease and Stroke Statistics 2011 Update: A Report from the American Heart Association.” Circulation, 2011;123;e18-e209. DOI: 10.1161/CIR.0b013e3182009701.
2. Huikuri HV, Castellanos A, Myerburg RJ. “Sudden death due to cardiac Arrhythmias.” N Engl J Med, 2001;345:1473– 82.
3. Verrier RL, Klingenheben T, Malik M, El-Sherif N, Exner D, Hohnloser S, Ikeda T, Martinez JP, Narayan S, Nieminen T, Rosenbaum DS. ”Microvolt T-wave Alternans: Physiologic Basis, Methods of Measurement, and Clinical Utility.” Consensus guideline by the International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol, 2011; 44:1309-1324. PMID:21920259. doi:10.1016/j.jacc.2011.06.029
4. Verrier RL, Nieminen T. “T-Wave Alternans as a Therapeutic Marker for Antiarrhythmic Agents.” J Cardiovasc Pharmacol, 2010;55:544–54.
5. Zipes DP, Camm AJ, Borggrefe M, et al. “ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines.” J Am Coll Cardiol, 2006;48:e247–346.