DIAGNOSTIC METHODS VENTRICULARA Electrical alternans and cardiac electrical instability

We investigated the relationship between electrical alternans and cardiac electrical stability in a series of 20 dog experiments and in a pilot clinical study. Electrical alternans was detected in both the QRS complex and the ST-T wave by use of a novel multidimensional spectral technique. The magnitude of the alternation was expressed as the alternating electrocardiographic morphology index (AEMI), expressed as parts per million of waveform energy. Electrical stability in the dog preparations was assessed via the ventricular fibrillation threshold measurement, and in the clinical studies via programmed stimulation. In 10 dog experiments, systemic hypothermia resulted in a 60% decrease in ventricular fibrillation threshold (VFT) (p < .0001) and a significant increase in both AEMI(QRS) from 3.7 + 3.0 to 1448 + 548 (p < .0001) and AEMI(ST-T) from 43.9 + 18.4 to 19,178 ± 5579 (p < .0001). In 10 dog experiments, transient coronary artery ligation also resulted in a 60% decrease in VFT (p < .0001). an increase from 76.3 ± 46.5 to 245 ± 11 in AEMI(QRS) (p < .05), and an increase from 842 + 505 to 1365 ± 392 in AEMI(ST-T) (p < .002). In 119 observations in 20 animal experiments, the rank correlation between VFT and AEMI(QRS) was .30 (p < .001), with that between VFT and AEMI(ST-T) being .55 (p < .0001). In a double-blind pilot clinical trial consisting of 23 studies in 19 patients, the result of electrophysiologic testing was used as an independent measure of cardiac electrical stability. Alternation in waveform morphology identified the inducible patient population with a sensitivity of 92%, a positive predictivity of 70%, and a specificity of 50% (p < .05). We conclude that analysis of subtle beat-to-beat variability in electrocardiographic morphology may provide a noninvasive measure of cardiac electrical stability. Circulation 77, No. 1, 110-121, 1988. IN THE LAST FEW YEARS, there has been great interest in the study of chaotic behavior in nonlinear systems. Particular interest has been focused on the description of system behavior during the transition from stable to chaotic regimes. One intriguing result has been the description of a "universal" period-doubling route to chaos, suggesting that a diverse set of complex dynamical systems approach their chaotic regimes through a universal pathway.1-3 The touchstones along this common route to chaos are perioddoubling or subharmonic bifurcations. A system driven at a fixed frequency w begins to demonstrate From Harvard-MIT Division of Health Sciences and Technology, Cambridge, Naval Blood Research Laboratory of the Boston University School of Medicine, the Department of Cardiology, Massachusetts General Hospital, Boston, and Department of Medicine, Brigham and Women's Hospital, Boston. Supported by NAS grant NAG2-327, ONR grant 00014-80-C-0520, award F33615-84-C-0601 from USAF School of Aerospace Medicine, and ONR contract N00014-79-C-0168 to the Naval Blood Research Laboratory, Boston. Address for correspondence: Dr. Joseph M. Smith, Harvard-MIT Division of Health Sciences and Technology, MIT-E25-330A. Cambridge, MA 02139. Received May 27. 1987; revision accepted Oct. 8, 1987. 110 excitations at subharmonics of the driving frequency as it approaches its chaotic regime, first w/2, then w/4, w/8, cv/16, etc., until the system finally enters the aperiodic chaotic regime. The spread of electrical excitation throughout the ventricular myocardium constitutes a complex, highly nonlinear physical process. This system is driven quasiperiodically by spontaneous electrical excitation, normally originating in the sinus node. The driving frequency is the heart rate itself. Electrical alternans may therefore be viewed as the first subharmonic bifurcation of this process, constituting an excitation at one-half of the driving frequency. Electrical alternans refers to variation in electrocardiographic (ECG) waveform morphology on an every-other-beat basis, i.e., an ABABA. . . pattern. In this context, electrical alternans might be interpreted as a marker that the system of cardiac electrical activation is approaching its chaotic regime, characterized by reentrant rhythm disturbances such as ventricular tachycardia and fibrillation. Electrical alternation in ECG complex morphology may result from mechanical "flip-flopping" of the heart CIRCULATION by gest on A ril 3, 2017 http://ciajournals.org/ D ow nladed from DIAGNOSTIC METHODS-VENTRICULAR ARRHYTHMIA on a beat-to-beat basis, as occurs with pericardial effusion and tamponade.f6 This form of electrical alternans is believed to result from mechanical movement of the heart within the pericardial sac, as opposed to a specific electrophysiologic abnormality. Electrical alternans has also been linked to prolonged QT syndromes,7-10 paroxysmal tachycardia, 11-14 bradycardia, 14' 15 exercise testing,16' 17 cardioactive drug therapy,'8' 19 WolffParkinson-White syndrome,20' 21 various intoxica22-24 22728 tions, electrolyte imbalances, 2227 hypothermia, coronary artery spasm,29-33 and coronary artery occlusion.28' 3438 Clinical observations have been made of increased incidence of electrical alternans and spontaneous ventricular fibrillation in patients with either of the prolonged QT syndromes7' 8 and in patients 29, 30, 32,33bera with Prinzmetal's angina. These observa tions suggest that electrical alternans may be caused by electrophysiologic alterations, and that this form ofelectrical alternans may be related to cardiac electrical instability. For the remainder of this discussion, we will focus on this form of primary electrical alternans as opposed to electrical alternans secondary to mechanical movement ofthe heart. As will be subsequently discussed, our methods of analysis are designed to minimize the effects of mechanical alternation resulting from beat-to-beat cardiac rotation. Recent work in our laboratory has demonstrated that finite-element models of cardiac conduction processes display alternation in synthesized ECG waveforms as these models are made increasingly unstable.39 40 In these models, subpopulations of sites with prolonged refractory periods may respond to every other stimulation, leading to alternate patterns of excitation and recovery in successive beats, thus giving rise to macroscopically observable electrical alternans. These subpopulations provide evanescent barriers to conduction, which facilitate wavefront fractionation and reentry, thus linking the mechanisms of formation of electrical alternans and reentrant arrhythmogenesis. The first quantitative study attempting to relate electrical alternans with myocardial electrical stability demonstrated that electrical alternans in vivo may be so subtle as to preclude visual detection, yet be statistically significant and easily measurable with digital signal processing techniques.28 That study was restricted to an examination of T wave alternans and focused on alternation in waveform energy, demonstrating that within a single experimental preparation, a relative increase in the amount of alternans detected was accompanied by a relative decrease in the measured ventricular fibrillation threshold (VFT). Vol. 77, No. 1, January 1988 Waveform energy, however, is a degenerate metric waveform morphology in the sense that an infinite number of waveforms may have the same energy. As a result, the study of waveform energy can be insensitive to morphologic variation if the overall energy of the waveform is largely unaffected. In extending that initial study, we have developed a nondegenerate multivariate spectral analysis procedure to quantify the degree and statistical significance of waveform alternation present in the magnitude of the three orthogonal-lead electrocardiogram, and have expanded the analysis to include both QRS and ST-T wave morphology. In this article we report on the relationship between electrical alternaus and electrical stability in experimental models of both acute coronary artery ligation and systemic hypothermia. We also report on a preliminary clinical study probing the relationship between ECG waveform alternation and the results of immediately subsequent electrophysiologic (EP) testing.