In spite of important advances in cardiology in recent years, pharmacological control of cardiac arrhythmias in the clinic remains an experiment conducted on a patient-by-patient basis using a trial and error approach tempered by good clinical judgment. Treatment, especially of life-threatening ventricular arrhythmias, remains largely empiric today because of our lack of understanding of the complex pathophysiological processes that give rise to cardiac rhythm disturbances. The problem is compounded by our incomplete understanding of the mechanisms by which antiarrhythmic agents act to suppress and in some cases aggravate arrhythmias. Also confounding is the lack of criteria that can be applied to the differential diagnosis of specific arrhythmia mechanisms in the clinic. Differential diagnosis of cardiac arrhythmias requires an understanding of basic mechanisms and establishment of mechanism-specific electrophysiological criteria. Both in turn depend on our knowledge of the basic electrophysiological characteristics of the cells and tissues of the heart and the extent to which heterogeneity or specialization exists. Our ability to design specific drug treatments also depends on our understanding and awareness of differences in the pharmacological responsiveness of diverse cell types within the heart. Until recently, most investigations of the electrophysiology and pharmacology of the ventricles focused on two main cell types, namely, ventricular myocardium and Purkinje fibers (or conducting tissues). Recent studies have provided data supporting the existence of at least four functionally distinct cell types in the canine ventricle, each with a characteristic electrophysiological and pharmacological pro-

Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells.

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.

Electrical alternans and cardiac electrical instability.

The restitution kinetics of action potential duration (APD) were investigated in paced canine Purkinje fibers (P;n = 9) and endocardial muscle (M; n = 9), in isolated, perfused canine left ventricl...

Dynamic restitution of action potential duration during electrical alternans and ventricular fibrillation

A link is found between T wave alternans and vulnerability to ventricular fibrillation, and a new approach is provided for quantification of susceptibility to malignant arrhythmias. Complex demodulation reveals that alternation of the electrocardiogram is concentrated during the first half of the T wave, coinciding with the vulnerable period of the cardiac cycle. During myocardial ischemia and reperfusion, there are marked increases in the degree of T wave alternans that parallel the established time course of changes in vulnerability. The influence of the sympathetic nervous system in arrhythmogenesis is also accurately detected. Ultimately, complex demodulation of the electrocardiogram could provide a technique for identification and management of individuals at risk for sudden cardiac death.

https://science.sciencemag.org/content/sci/252/5004/437.full.pdf

Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave.

The effects of acute global ischemia on cytosolic calcium transients were studied in perfused rabbit hearts loaded with the fluorescent calcium indicator indo 1. Indo 1-loaded hearts were illuminated at 360 nm, and fluorescence was recorded simultaneously at 400 and 550 nm from the epicardial surface of the left ventricle. The F400/F550 ratio was calculated by an analog circuit, which allowed cancellation of optical motion artifact. Resulting calcium transients demonstrated a rapid upstroke and slow decay similar to those recorded in isolated ventricular myocytes. Global ischemia rapidly suppressed contraction, but it produced a concurrent increase in the systolic and diastolic levels of the calcium transients, together with an increase in the duration of the peak. The effects of ischemia were reversed by reperfusion, inhibited by verapamil, and mimicked by perfusion of nonischemic hearts with acidified (CO2-rich) solution. In addition to elevation of the calcium transients, ischemia caused a pattern of intracellular calcium alternans that was discernible after 2-3 minutes. The pattern of alternans was stable at a given epicardial site, but it could be out of phase at different sites. Similar nonuniformities were observed in contraction strength and in the duration of monophasic action potentials recorded immediately adjacent to the fiber-optic probe. Abnormalities in intracellular calcium may be a causal factor in the loss of electrical and mechanical synchrony in the acutely ischemic heart.

Effect of ischemia on calcium-dependent fluorescence transients in rabbit hearts containing indo 1. Correlation with monophasic action potentials and contraction.

Electrophysiological changes occurring soon after experimental coronary occlusion have been examined in 13 dogs by combined recording of epicardial action potential, endocardial-epicardial conduction time, and epicardial ST segment elevation during successive 5-minute occlusions of the left anterior descending coronary artery. Mter initial coronary occlusion, action potential duration shortened from 182 ± 9 ms to 113 ± 9 ms at 2 minutes and conduction time was prolonged from 24 i 1 ms to 71 ± 17 ms associated with progressive ST segment elevation. These changes were followed by the appearance of potentials of 'slow response' type morphology, alternans of action potential duration and amplitude, alternans of epicardial and endocardial ST segment elevation, and intermittent conduction block. Ventricular fibrillation was preceded by action potential alternans in 95 per cent and by conduction block in 65 per cent of instances and occurred at a time of maximum conduction delay. These data strongly support the concept of re-entry in the pathogenesis of early ventricular fibrillation. Changes in action potential duration and conduction time were significantly greater during the first occlusion compared with subsequent occlusion periods. There was no significant difference however between data taken from occlusions 2, 3, 4, or 5. This questions the validity of experimental studies of myocardial ischaemia based on comparisons of sequential coronary occlusions using the first as the control.

https://heart.bmj.com/content/heartjnl/42/1/88.full.pdf

D C Russell

Papers

Transmembrane potential changes and ventricular fibrillation during repetitive myocardial ischaemia in the dog.