Cellular Basis for the Electrocardiographic J Wave
TL;DR: The results provide the first direct evidence in support of the hypothesis that heterogeneous distribution of a transient outward current-mediated spike-and-dome morphology of the action potential across the ventricular wall underlies the manifestation of the electrocardiographic J wave.
Abstract: Background The J wave is a deflection that appears in the ECG as a late delta wave following the QRS or as a small secondary R wave (R′). Also referred to as an Osborn wave, the J wave has been observed in the ECG of animals and humans for more than four decades, yet the mechanism underlying its manifestation is poorly understood. The present study investigates the cellular basis for the J wave using an isolated arterially perfused preparation consisting of a wedge of canine right or left ventricle. Methods and Results A 12-lead ECG was initially recorded in vivo. After isolation and arterial perfusion of the right or left ventricular wedge, transmembrane action potentials were simultaneously recorded from epicardial, M region, and endocardial transmural sites with three floating microelectrodes. A transmural ECG was recorded concurrently. A J wave was observed at the R-ST junction of the ECG in 17 of 20 adult dogs, usually in leads II, III, aVR, and aVF and the mid to lateral precordial leads. The J wave...
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TL;DR: It is shown that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional.
Abstract: Ventricular fibrillation causes more than 300,000 sudden deaths each year in the USA alone. In approximately 5-12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.
1,717 citations
TL;DR: Depression or loss of the action potential dome in RV epicardium creates a transmural voltage gradient that may be responsible for the ST-segment elevation observed in the Brugada syndrome and other syndromes exhibiting similar ECG manifestations.
Abstract: Background—The Brugada syndrome is characterized by marked ST-segment elevation in the right precordial ECG leads and is associated with a high incidence of sudden and unexpected arrhythmic death. Our study examines the cellular basis for this syndrome. Methods and Results—Using arterially perfused wedges of canine right ventricle (RV), we simultaneously recorded transmembrane action potentials from 2 epicardial and 1 endocardial sites, together with unipolar electrograms and a transmural ECG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 μmol/L), a K+ channel opener, or the combination of a Na+ channel blocker (flecainide, 7 μmol/L) and acetylcholine (ACh, 2 to 3 μmol/L) resulted in an abbreviation of epicardial response and a transmural dispersion of repolarization, which caused an ST-segment elevation in the ECG. ACh facilitated loss of the action potential dome, whereas isoproterenol (0.1 to 1 μmol/L) restored the epicardial dome, thus reducing...
1,078 citations
TL;DR: A model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is developed and experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undISEased human myocytes were quantitatively reproduced by the model.
Abstract: Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca2+ versus voltage dependent inactivation of L-type Ca2+ current (ICaL); kinetics for the transient outward, rapid delayed rectifier (IKr), Na+/Ca2+ exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by IKr block during slow pacing, and AP and Ca2+ alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling. INaCa linked Ca2+ alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na+]i, via its modulation of the electrogenic Na+/K+ ATPase current. At fast pacing rates, late Na+ current and ICaL were also contributors. APD shortening during restitution was primarily dependent on reduced late Na+ and ICaL currents due to inactivation at short diastolic intervals, with additional contribution from elevated IKr due to incomplete deactivation.
1,012 citations
TL;DR: The authors' data suggest that the "pathophysiological U" wave observed in acquired or congenital LQTS is more likely to be a second component of an interrupted T wave, and argue for use of the term T2 in place of U to describe this event.
Abstract: Background—This study probes the cellular basis for the T wave under baseline and long-QT (LQT) conditions using an arterially perfused canine left ventricular (LV) wedge preparation, which permits direct temporal correlation of cellular transmembrane and ECG events. Methods and Results—Floating microelectrodes were used to record transmembrane action potentials (APs) simultaneously from epicardial, M-region, and endocardial sites or subendocardial Purkinje fibers. A transmural ECG was recorded concurrently. Under baseline and LQT conditions, repolarization of the epicardial action potential, the earliest to repolarize, coincided with the peak of the T wave; repolarization of the M cells, the last to repolarize, coincided with the end of the T wave. Thus, the action potential duration (APD) of the longest M cells determine the QT interval and the Tpeak–Tend interval serves as an index of transmural dispersion of repolarization. Repolarization of Purkinje fibers outlasted that of the M cell but failed to r...
939 citations
TL;DR: An early-repolarization pattern in the inferior leads of a standard electrocardiogram is associated with an increased risk of death from cardiac causes in middle-aged subjects.
Abstract: Background Early repolarization, which is characterized by an elevation of the QRS–ST junction (J point) in leads other than V1 through V3 on 12-lead electrocardiography, has been associated with vulnerability to ventricular fibrillation, but little is known about the prognostic significance of this pattern in the general population. Methods We assessed the prevalence and prognostic significance of early repolarization on 12-lead electrocardiography in a community-based general population of 10,864 middle-aged subjects (mean [±SD] age, 44±8 years). The primary end point was death from cardiac causes, and secondary end points were death from any cause and death from arrhythmia during a mean follow-up of 30±11 years. Early repolarization was stratified according to the degree of J-point elevation (≥0.1 mV or >0.2 mV) in either inferior or lateral leads. Results The early-repolarization pattern of 0.1 mV or more was present in 630 subjects (5.8%): 384 (3.5%) in inferior leads and 262 (2.4%) in lateral leads,...
782 citations
References
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TL;DR: Common clinical and ECG features define a distinct syndrome in this group of patients with recurrent episodes of aborted sudden death unexplainable by currently known diseases, not explainable by electrolyte disturbances, ischemia or structural heart disease.
3,075 citations
TL;DR: 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.
Abstract: 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-
747 citations
TL;DR: Researchers report here studies on single channel currents recorded from heart muscle cells, in which they have found a channel, abundant in cardiac membrane, which does not seem to belong in any of the familiar categories.
Abstract: Present concepts of excitable membrane function are based primarily on knowledge of two classes of channels: those activated by neurotransmitters1 and those activated by membrane potential2. Recent evidence suggests that these notions may have to be modified to include other channel types, such as special ion channels activated by membrane potential but regulated by ligands3–5. We report here studies on single channel currents recorded from heart muscle cells, in which we have found a channel, abundant in cardiac membrane, which does not seem to belong in any of the familiar categories. This channel shows little selectivity between cations, but excludes anions. It is activated by intracellular Ca ions but is not appreciably affected by membrane potential.
662 citations
TL;DR: The results suggest that the distinctive phase-3 repolarization features of M cells are due in part to a lesser contribution of IKs and that this distinction may also explain why M Cells are the main targets for agents that prolong APD in ventricular myocardium.
Abstract: Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. In this study, we use standard microelectrode and whole-cell patch-clamp techniques to examine the characteristics of the action potential and the delayed rectifier K+ current (IK) in epicardial, M region (deep subepicardial to midmyocardial), and endocardial cells isolated from the canine left ventricle. Cells from the M region displayed much longer action potential durations (APDs) at slow rates. At a basic cycle length of 4 s, APD measured at 90% repolarization was 358 +/- 16 (mean +/- SEM), 262 +/- 12, and 287 +/- 11 ms in cells from the M region, epicardium, and endocardium, respectively. Steady state APD-rate relations were steeper in cells from the M region. In complete Tyrode's solution, IK was smaller in myocytes from the M region when compared with those isolated from the epicardium or endocardium. Further characterization of IK was conducted in a Na(+)-, K(+)-, and Ca(2+)-free bath solution to isolate the slowly activating component of the delayed rectifier (IKs) from the rapidly activating component (IKr). IKs was significantly smaller in M cells than in epicardial and endocardial cells. With repolarization to -20 mV, IKs tail current density was 1.99 +/- 0.30 pA/pF (mean +/- SEM) in epicardial cells, 1.83 +/- 0.18 pA/pF in endocardial cells, and 0.92 +/- 0.14 pA/pF in M cells. Voltage dependence and time course of activation and deactivation of IKs were similar in the three cell types. The relative contribution of IKr and IKs among the three cell types was examined by using 6 mmol/L [K+]o Tyrode's solution with and without E-4031, a highly selective blocker of IKr. An E-4031-sensitive current was observed in the presence but not in the absence of extracellular K+. This rapidly activating component showed characteristics similar to those of IKr as described in rabbit and cat ventricular cells. Deactivation of IKr was significantly slower than that of IKs. IKr (E-4031-sensitive component) tail current density was similar in the three cell types, whereas IKs (E-4031-insensitive component) tail current density was significantly smaller in the M cells. Our results suggest that the distinctive phase-3 repolarization features of M cells are due in part to a lesser contribution of IKs and that this distinction may also explain why M cells are the main targets for agents that prolong APD in ventricular myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)
627 citations
TL;DR: It is proposed that the parallel orientation of the muscle bundles in the epicardial border zone is an important cause of ventricular tachycardia because activation transverse to myocardial fibers is sufficiently slow to permit the occurrence of reentry.
Abstract: Excitation in the epicardial border zone of 3-5-day-old canine infarcts was mapped with an array of 192 bipolar electrodes during sustained ventricular tachycardia. Reentrant circuits were found in which activation occurred around long lines of apparent conduction block based on the criterion that excitation on opposite sides of the lines occurred with marked disparity in time. When the lines of apparent block were functional (i.e., occurred only during tachycardia and not during sinus rhythm or ventricular pacing) they were oriented parallel to the long axis of epicardial muscle fiber bundles. Isochrones distal to the lines were oriented parallel to them because widely separate sites within these isochrones were activated nearly simultaneously. This suggested that excitation not only occurred around the lines of block but also slowly across them. This slow activation occurred transverse to the long axis of the myocardial fibers and therefore might result because of the anisotropic tissue properties. To test this hypothesis, the epicardial border zone was stimulated during sinus rhythm through electrodes around its margin and at the center of the recording array. Activation transverse to the myocardial fibers in regions where lines of block occurred during tachycardia was slow, whereas it was rapid parallel to fibers' orientation. During tachycardia electrograms along the lines of apparent block had long durations and were fractionated, a characteristic that can also result from activation transverse to the myocardial fiber long axis. Therefore, we propose that the parallel orientation of the muscle bundles in the epicardial border zone is an important cause of ventricular tachycardia because activation transverse to myocardial fibers is sufficiently slow to permit the occurrence of reentry.
526 citations