Francis X. Witkowski

Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium.

Lysophosphoglycerides, products of membrane phospholipid catabolism known to influence membrane function in several systems, appeared in the effluents of anoxic isolated rabbit hearts perfused at low flow and accumulated in perfused hearts and myocardium rendered ischemic in situ. Comparable concentrations of lysophosphoglycerides bound to albumin markedly and reversibly altered action potentials of isolated canine Purkinje fibers in vitro. Changes induced included diminution of the maximum diastolic potential, peak dV/dt of phase zero, amplitude, and action potential duration--alterations resembling those seen in ischemic myocardium in vivo. These electrophysiological alterations are compatible with changes implicated in predisposing to dysrhythmia dependent on reentry, a phenomenon potentiated by the presence of zones of decreased conduction. Thus, accumulation of lysophosphoglycerides induced by ischemia may contribute to the genesis of malignant dysrhythmia early after its onset.

Fast-Fourier transform analysis of signal-averaged electrocardiograms for identification of patients prone to sustained ventricular tachycardia.

Electrocardiograms obtained from patients during arrhythmia-free intervals do not identify those prone to sustained ventricular tachycardia (VT) despite the occult delayed activation that is presumably present. To determine whether frequency-domain analysis facilitates detection of this hallmark of predisposition to VT, fast-Fourier transform analysis (FFTA) procedures were developed and tested with a computer-generated mathematical model. The FFTA approach developed allows inherent limitations of high-gain amplification and a priori filtering used commonly for time-domain analysis to be avoided. After demonstrating that FFTA detected low-amplitude oscillatory waveforms in signal-averaged recordings in the frequency domain, the procedure was applied to signal-averaged X, Y, and Z lead recordings from the following three groups of patients: group I, patients with prior myocardial infarction and episodic sustained VT (n = 16); group II, patients with prior myocardial infarction without overt sustained VT (n = 35); and group III, normal control subjects (n = 10). Results of FFTA demonstrated significant (p less than .0001) differences in the decibel drop at 40 Hz and the area under the curve from the fundamental frequency to the frequency at which the spectral amplitude was decreased by 60 dB for both the terminal 40 msec of the QRS and ST segment in patients in group I compared with those in groups II and III, in whom results were similar. Results were independent of QRS duration (r = .2), left ventricular ejection fraction (r = .19), and complexity of spontaneous ventricular ectopy. Thus, patients known to manifest sustained VT also exhibited relatively greater high-frequency content in arrhythmia-free intervals in the terminal QRS and ST segment than those without VT (88%, 15%, and 0% in groups I through III, respectively). FFTA offers promise for the noninvasive detection of patients at risk for the development of sustained VT.

Mechanisms Contributing to Malignant Dysrhythmias Induced by Ischemia in the Cat

Continuously recorded bipolar electrograms were obtained simultaneously from epi-, endo-, and mid-myocardial regions of the ischemic and normal zones of cat left ventricle in vivo after coronary occlusion, analyzed by computer, and compared to regional cyclic AMP levels. Regional cyclic AMP content was used as an index of the combined local effects of: (a) efferent sympathetic nerve discharge; (b) release of myocardial catecholamines due to ischemia; and (c) circulating catecholamines. Ischemia resulted in a progressive increase in pulse width and rise time and a decrease in rate of rise of voltage (dV/dt) of the local electrograms from ischemic zones reaching a maximum within 2.4+/-0.3 min (mean+/-SE) at the time of onset of severe ventricular dysrhythmias, all of which returned toward control before the cessation of the dysrhythmia (33.5+/-1.5 min after coronary occlusion). Increases in cyclic AMP in ischemic zones preceded corresponding increases in the frequency of premature ventricular complexes (PVCs). Propranolol inhibited the increases in cyclic AMP and reduced the frequency of PVCs in animals without ventricular fibrillation. In animals with ventricular fibrillation, cyclic AMP was significantly elevated in normal and ischemic zones compared to animals with PVCs only. Electrical induction of PVCs or ventricular fibrillation in ischemic and nonischemic hearts failed to increase cyclic AMP. The results suggest that the changes in regional adrenergic stimulation of the heart may contribute to perpetuation of ventricular dysrhythmia and the genesis of ventricular fibrillation early after the onset of myocardial ischemia.

Simultaneous computer mapping to facilitate intraoperative localization of accessory pathways in patients with Wolff-Parkinson-White syndrome

Sixteen patients with the Wolff-Parkinson-White syndrome underwent simultaneous intraoperative computer mapping from multiple sites before surgical division of the accessory pathways. A 16-bipolar electrode band was positioned around the atrioventricular groove. Ventricular epicardial electrograms from single beats were recorded simultaneously during atrial pacing, resulting in maximal preexcitation, and atrial electrograms were recorded during orthodromic supraventricular tachycardia. Four-level transmural plunge needle electrodes were used concomitantly in 3 patients. Electrograms were processed separately using a guarded signal conditioner that isolates, amplifies, filters and analog-to-digitally converts synchronously at 2 kHz with 12-bit accuracy. Digital data were transmitted by fiber optics to a high-density digital recorder and processed with a computer having rapid interactive graphics. Results in the 16 patients revealed 20 distinct Kent bundles. Two patients had only nonsustained supraventricular tachycardia induced intraoperatively and 1 patient manifested intermittent anterograde ventricular preexcitation. Multiple pathways were identified in 4 patients. This simultaneous multiple electrode mapping procedure facilitates intraoperative mapping by requiring only a single beat for analysis of anterograde and retrograde activation times, decreases cardiac manipulation during mapping and obviates the need for cardiopulmonary bypass, and permits analysis of transmural activation patterns. This approach decreases markedly the time required for mapping and permits accurate study of nonsustained arrhythmias as well as rapid identification of multiple accessory pathways.

Arrhythmias associated with reperfusion: basic insights and clinical relevance.

Arrhythmias associated with reperfusion of is-chemic myocardium may be a major progenitor for sudden cardiac death in man. The electrophysiological basis for arrhythmias associated with reperfusion appears to be heterogenous electrical recovery, but the precise alterations responsible for malignant versus nonmalignant arrhythmias are unknown. In experimental animals, the highest incidence of malignant arrhythmias after reperfusion occurs after 20 to 30 min of preceding ischemia, a critical time period in which both reversibly and irreversibly injured cells are present, with reperfusion resulting in maximal heterogeneity of recovery of electrical parameters. Although changes in K+, Pco2, and intracellular Ca2+ may be critical in arrhythmogenesis during reperfusion, direct cause-and-effect relationships have not been established. Increases in both α-adrenergic responsivity and the density of α1-adrenergic receptors appear to mediate important influences on these malignant arrhythmias, including changes in intracellular calcium. Recent findings also suggest that the accumulation of lysophosphatides in ischemic myocardium may be the responsible moiety for the increase in α1-adrenergic receptors.

Barium decreases defibrillation energy requirements

Summary Certain antiarrhythmic drugs that inhibit myocardial repolarizing currents decrease defibrillation energy, but the effect of blocking particular currents on defibrillation is not well understood. We therefore investigated the effect of barium, a relatively selective blocker of inwardly rectifying potassium current (Ik1) on voltage and energy requirements for defibrillation in an open-chest dog model. Defibrillation energy and voltage requirements were assessed by delivering monophasic shocks through epicardial electrode patches at varying voltages to construct a dose-response curve of energy and voltage versus success in defibrillation. The energy and voltage for 50% success in defibrillation (E50 and V50, respectively) were determined by logistic regression. Monophasic action potential duration at 90% repolarization (MAPDgo) was measured with a contact electrode, and ventricular refractory period (VERP) was measured. After baseline measurements were obtained of A£so, VJ0, MAPD90, and VERP, saline (control) (n = 6) or barium (1.1 mg/kg/min for 5 min followed by 0.25 mg/kg/min) (n = 11) was administered. Defibrillation voltage and energy requirements and electrophysiologic measures were repeated after 30 and 120 min of barium or saline infusion. In control animals, there was no significant change with time in V50 (2.0 ± 12.4 and −0.2 ± 16.0% at 30 and 120 min, respectively), VERP ( + 3 ± 5 and −2 ± 3% at 30 and 120 min, respectively) or MAPD90 (+1 ± 4 and – 2 ± 6, at 30 and 120 min, respectively). In contrast, after barium infusion, there was a significant decrease in V50 both at 30 and 120 min (-21.8 ± 19.2, −36.2 ± 15.8%, p < 0.001), in E50 (decrease of −34.2 ± 38 and −59.9 ± 23% at 30 and 120 min, respectively, p < 0.001), and increases in VERP (+ 20 ± 4 and + 22 ± 4% at 30 and 120 min, p < 0.03) and in MAPD90 (+ 15 ± 6 and + 15 ± 4% at 30 and 120 min, p < 0.03). We conclude that relatively specific inhibition of inwardly rectifying potassium current markedly decreases defibrillation voltage and energy requirements at a dose that produces slight increases in ventricular refractoriness and MAPD.

Mechanisms responsible for arrhythmias associated with reperfusion of ischemic myocardium.

In experimental animals, both myocardial ischemia and reperfusion are each associated with malignant ventricular arrhythmias, the mechanisms for which appear to differ.l-1° The applicability of reperfusion to human arrhythmias, however, including sudden cardiac death, is controversial. In a large percentage of patients autopsied after sudden cerdiac death, there is an absence of complete coronary occlusions l1 suggesting that the lethal event may have followed an ischemic interval after subsequent reperfusion by way of one or more of the following mechanisms: spasm of a normal or partially obstructed coronary artery,12 platelet aggregation with thrombus formation and subsequent spontaneous lysis,13 and increases in collateral flow to an ischemic region.14 Similarly, recanalization using thrombolytic therapy in patients during acute myocardial infarction is also associated with ventricular arrhythmias, although their incidence and severity v a r i e ~ . l ~ ~ ~ The relatively low incidence of severe arrhythmias in patients after successful coronary thrombolysis compared to animal preparations may be related to a number of factors including the duration of preceding ischemia usually being much longer in patients; gradual, compared to sudden reperfusion; extent of ischemic damage, being more pronounced in patients due to the duration of the ischemic interval; and complete and rapid reflow in contrast to more partial reflow in patients. Indeed, a recent study indicates that during intracoronary thrombolysis in patients, the presence of ventricular arrhythmias is an indicator of the success of recanalization.20 In this brief review, we will consider both the electrophysiological and biochemical mechanisms that appear to underlie reperfusion-induced arrhythmias. The malignant arrhythmias associated with coronary occlusion, including both ventricular tachycardia (VT) and ventricular fibrillation (VF) , are usually preceded by gradual alterations in the electrical behavior of the ischemic and border regions. By contrast, arrhythmias induced by reperfusion usually occur within seconds, persist for a brief period, and frequently commence with the occurrence of ventricular fibrillation.8 Gradual, rather than rapid reperfusion has been shown to significantly attenuate the associated malignant ventricular

Epicardial cardiac source-field behavior

The accurate determination of the spatial distribution of cardiac electrophysiological state is essential for the mechanistic assessment of cardiac arrhythmias in both clinical and experimental cardiac electrophysiological laboratories. The authors describe three fundamental cardiac source-field relationships: 1) activation fields; 2) electrotonic fields; and 3) volume conductor fields. The three cases are described analytically and illustrated with experimentally obtained canine cardiac recordings that capitalize on a recently formulated technique for in vivo cardiac transmembrane current estimation.<<ETX>>

Development of a nonlinearly deterministic signal generator for real time chaos control testing

Chaotic dynamics have been successfully exploited in feedback control strategies. Recently, the authors have described the existence of unstable fixed points during ventricular fibrillation (VF), similar to those previously used in chaos control. Prior to embarking on control attempts of VF, a signal source was designed with known nonlinearly deterministic dynamics with well characterized stable and unstable manifolds as well as fixed point location. This ensured that the complex real-time data acquisition/analysis necessary to attempt such control was feasible for the interval durations typical of VF. A signal source was designed that can operate on any IBM compatible PC via the parallel port, and generates a waveform whose inter-event interval is nonlinearly deterministic with timing resolution of 0.1 /spl mu/sec with a range from 20 msec to 1.5 sec, independent of PC clock speed.