Richard J. Cohen

Electrical Alternans and Vulnerability to Ventricular Arrhythmias

BACKGROUND Although electrical alternans (alternating amplitude from beat to beat on the electrocardiogram) has been associated with ventricular arrhythmias in many clinical settings, its physiologic importance and prognostic implications remain unknown. METHODS To test the hypothesis that electrical alternans is a marker of vulnerability to ventricular arrhythmias, we developed a technique to detect subtle alternation in the morphologic features of the electrocardiogram (which would not be detectable by visual inspection of the electrocardiogram). In a group of 83 patients referred for diagnostic electrophysiologic testing, we prospectively examined whether levels of alternans predicted vulnerability to arrhythmias as defined by the outcome of electrophysiologic testing and arrhythmia-free survival. RESULTS Sustained ventricular arrhythmias were induced during electrophysiologic testing in 32 of the patients (39 percent). In this group, low-level electrical alternans (a beat-to-beat change in amplitude of < 15 microV) was detected over a broad range of physiologic heart rates (from 95 to 150 beats per minute) and primarily involved the ST segment and the T wave (i.e., the phase of repolarization). Alternans during repolarization was a significant and independent predictor of inducible arrhythmias on electrophysiologic testing (sensitivity, 81 percent; specificity, 84 percent; relative risk, 5.2). Of 66 patients followed for up to 20 months, 13 had arrhythmic events. Alternans affecting the T wave and inducibility of ventricular arrhythmias were significant and essentially equivalent predictors of survival without arrhythmia (P < 0.001). Actuarial survival without arrhythmia at 20 months was significantly lower among the patients with T-wave alternans (19 percent) than among the patients without T-wave alternans (94 percent). CONCLUSIONS Electrical alternans affecting the ST segment and T wave is common among patients at increased risk for ventricular arrhythmias. Subtle electrical alternans on the electrocardiogram may serve as a noninvasive marker of vulnerability to ventricular arrhythmias.

An Efficient Algorithm for Spectral Analysis of Heart Rate Variability

We present a simple efficient algorithm for the derivation of a heart rate signal from the electrocardiogram. We demonstrate that the amplitude spectrum of this heart rate signal more closely matches that of the input signal to an integral pulse frequency modulation (IPFM) model of the hearts pacemaker than do the spectra of other ECG-derived heart rate signals. The applicability of this algorithm in cross-spectral analysis between heart rate and other physiologic signals is also discussed.

Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis.

Neurohumoral modulation of cardiovascular function is an important component of the hemodynamic alterations in patients with chronic congestive heart failure (CHF). Analysis of heart rate (HR) variability is a noninvasive means of investigating the autonomic control of the heart. The variability of HR and respiratory signals, both derived from ambulatory electrocardiographic recordings, were analyzed with power spectral analysis to evaluate autonomic control in 25 patients with chronic stable CHF (class III or IV) and 21 normal control subjects. In the patients with CHF, HR spectral power was markedly reduced (p less than 0.0001) at all frequencies examined (0.01 to 1.0 Hz, period 1 to 100 seconds) and virtually absent at frequencies greater than 0.04 Hz. Heart rate fluctuations at very low frequencies (0.01 to 0.04 Hz) less effectively differentiated CHF patients from control subjects, due to discrete (about 65 seconds, 0.015 Hz) oscillation in HR, which was associated with a similar pattern in respiratory activity in many of the patients with CHF. These findings demonstrate a marked derangement of HR modulation in patients with severe CHF. The frequency characteristics of HR fluctuations in these patients are consistent with abnormal baroreflex responsiveness to physiologic stimuli, and suggest that there is diminished vagal, but relatively preserved sympathetic, modulation of HR.

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 alteration 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 less than .0001) and a significant increase in both AEMI(QRS) form 3.7 +/- 3.0 to 1448 +/- 548 (p less than .0001) and AEMI(ST-T) from 43.9 +/- 18.4 to 19,178 +/- 5579 (p less than .0001). In 10 dog experiments, transient coronary artery ligation also resulted in a 60% decrease in VFT (p less than .0001), an increase from 76.3 +/- 46.5 to 245 +/- 11 in AEMI(QRS) (p less than .05), and an increase from 842 +/- 505 to 1365 +/- 392 in AEMI(ST-T) (p less than .002). In 119 observations in 20 animal experiments, the rank correlation between VFT and AEMI(QRS) was -.30 (p less than .001), with that between VFT and AEMI(ST-T) being -.55 (p less than .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 less than .05). We conclude that analysis of subtle beat-to-beat variability in electrocardiographic morphology may provide a noninvasive measure of cardiac electrical stability.

Beat to beat variability in cardiovascular variables: noise or music?

Cardiovascular variables such as heart rate, arterial blood pressure, stroke volume and the shape of electrocardiographic complexes all fluctuate on a beat to beat basis. These fluctuations have traditionally been ignored or, at best, treated as noise to be averaged out. The variability in cardiovascular signals reflects the homeodynamic interplay between perturbations to cardiovascular function and the dynamic response of the cardiovascular regulatory systems. Modern signal processing techniques provide a means of analyzing beat to beat fluctuations in cardiovascular signals, so as to permit a quantitative, noninvasive or minimally invasive method of assessing closed loop hemodynamic regulation and cardiac electrical stability. This method promises to provide a new approach to the clinical diagnosis and management of alterations in cardiovascular regulation and stability.

Power Law Behavior of RR-Interval Variability in Healthy Middle-Aged Persons, Patients With Recent Acute Myocardial Infarction, and Patients With Heart Transplants

BACKGROUND The purposes of the present study were (1) to establish normal values for the regression of log(power) on log(frequency) for, RR-interval fluctuations in healthy middle-aged persons, (2) to determine the effects of myocardial infarction on the regression of log(power) on log(frequency), (3) to determine the effect of cardiac denervation on the regression of log(power) on log(frequency), and (4) to assess the ability of power law regression parameters to predict death after myocardial infarction. METHODS AND RESULTS We studied three groups: (1) 715 patients with recent myocardial infarction; (2) 274 healthy persons age and sex matched to the infarct sample; and (3) 19 patients with heart transplants. Twenty-four-hour RR-interval power spectra were computed using fast Fourier transforms and log(power) was regressed on log(frequency) between 10(-4) and 10(-2) Hz. There was a power law relation between log(power) and log(frequency). That is, the function described a descending straight line that had a slope of approximately -1 in healthy subjects. For the myocardial infarction group, the regression line for log(power) on log(frequency) was shifted downward and had a steeper negative slope (-1.15). The transplant (denervated) group showed a larger downward shift in the regression line and a much steeper negative slope (-2.08). The correlation between traditional power spectral bands and slope was weak, and that with log(power) at 10(-4) Hz was only moderate. Slope and log(power) at 10(-4) Hz were used to predict mortality and were compared with the predictive value of traditional power spectral bands. Slope and log(power) at 10(-4) Hz were excellent predictors of all-cause mortality or arrhythmic death. To optimize the prediction of death, we calculated a log(power) intercept that was uncorrelated with the slope of the power law regression line. We found that the combination of slope and zero-correlation log(power) was an outstanding predictor, with a relative risk of > 10, and was better than any combination of the traditional power spectral bands. The combination of slope and log(power) at 10(-4) Hz also was an excellent predictor of death after myocardial infarction. CONCLUSIONS Myocardial infarction or denervation of the heart causes a steeper slope and decreased height of the power law regression relation between log(power) and log(frequency) of RR-interval fluctuations. Individually and, especially, combined, the power law regression parameters are excellent predictors of death of any cause or arrhythmic death and predict these outcomes better than the traditional power spectral bands.

Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure

Measurement of microvolt level T-wave alternans in the surface electrocardiogram is a novel way to assess the risk of ventricular arrhythmias. Seven tests of arrhythmic risk, including T-wave alternans, were undertaken in 107 consecutive patients with congestive heart failure and no history of sustained ventricular arrhythmias; the patients were followed up for arrhythmic events during the next 18 months. Of the patients with events, 11 had positive and two indeterminate T-wave alternans results; there were no arrhythmic events among patients with negative T-wave alternans results. Of the seven tests, only T-wave alternans was a significant (p=0.0036) and independent predictor of arrhythmic events.

Cardiac muscle tissue engineering: toward an in vitro model for electrophysiological studies

The objective of this study was to establish a three-dimensional (3-D) in vitro model system of cardiac muscle for electrophysiological studies. Primary neonatal rat ventricular cells containing lower or higher fractions of cardiac myocytes were cultured on polymeric scaffolds in bioreactors to form regular or enriched cardiac muscle constructs, respectively. After 1 wk, all constructs contained a peripheral tissue-like region (50-70 micrometer thick) in which differentiated cardiac myocytes were organized in multiple layers in a 3-D configuration. Indexes of cell size (protein/DNA) and metabolic activity (tetrazolium conversion/DNA) were similar for constructs and neonatal rat ventricles. Electrophysiological studies conducted using a linear array of extracellular electrodes showed that the peripheral region of constructs exhibited relatively homogeneous electrical properties and sustained macroscopically continuous impulse propagation on a centimeter-size scale. Electrophysiological properties of enriched constructs were superior to those of regular constructs but inferior to those of native ventricles. These results demonstrate that 3-D cardiac muscle constructs can be engineered with cardiac-specific structural and electrophysiological properties and used for in vitro impulse propagation studies.The objective of this study was to establish a three-dimensional (3-D) in vitro model system of cardiac muscle for electrophysiological studies. Primary neonatal rat ventricular cells containing lower or higher fractions of cardiac myocytes were cultured on polymeric scaffolds in bioreactors to form regular or enriched cardiac muscle constructs, respectively. After 1 wk, all constructs contained a peripheral tissue-like region (50-70 μm thick) in which differentiated cardiac myocytes were organized in multiple layers in a 3-D configuration. Indexes of cell size (protein/DNA) and metabolic activity (tetrazolium conversion/DNA) were similar for constructs and neonatal rat ventricles. Electrophysiological studies conducted using a linear array of extracellular electrodes showed that the peripheral region of constructs exhibited relatively homogeneous electrical properties and sustained macroscopically continuous impulse propagation on a centimeter-size scale. Electrophysiological properties of enriched constructs were superior to those of regular constructs but inferior to those of native ventricles. These results demonstrate that 3-D cardiac muscle constructs can be engineered with cardiac-specific structural and electrophysiological properties and used for in vitro impulse propagation studies.

Interpretation and Classification of Microvolt T Wave Alternans Tests

Interpretation of T Wave Alternans Tests. Measurement of microvolt‐level T wave alternans (TWA) during routine exercise stress testing now is possible as a result of sophisticated noise reduction techniques and analytic methods that have become commercially available. Even though this technology is new, the available data suggest that microvolt TWA is a potent predictor of arrhythmia risk in diverse disease states. As this technology becomes more widely available, physicians will be called upon to interpret microvolt TWA tracings. This review seeks to establish uniform standards for the clinical interpretation of microvolt TWA tracings.

Kinetics and affinity of reactions between an antigen-specific T cell receptor and peptide-MHC complexes

We show here that the net rate of accumulation of complexes formed by the antigen-specific receptor of T cells (TCR) of a T cell clone with its natural ligand, an octapeptide in association with Ld, a class I protein of the major histocompatibility complex (MHC), approaches the maximal value determined by the affinity of the TCR for this peptide-MHC ligand in 1-2 min, which is well within the lifetime of transient T cell-target cell conjugates. Consistent with this finding, we also found that the widely divergent affinity values (equilibrium constants) of this TCR for six related peptide-MHC complexes correlate well with the extent of specific lysis of target cells bearing various level of these complexes.