Drug-Induced Afterdepolarizations and Triggered Activity Occur in a Discrete Subpopulation of Ventricular Muscle Cells (M Cells) in the Canine Heart:

EADs and DADs in M Cells. Introduction: Oscillations of membrane potential that attend or follow the cardiac action potential and depend on preceding Tran membrane activity for their manifestation are known as aflerdepolarizations. Early aflerdepolarizations (EADs) interrupt or retard repolarization of the cardiac action potential, whereas delayed afterdepolarizations (DADs) arise after full repolarization. EADs and DADs can give rise to spontaneous action potentials or triggered activity believed to be responsible for a variety of cardiac arrhythmias. Recent studies from our laboratory have highlighted differences in the electrophysiology and pharmacology of three functionally distinct myocardial cell types found in the canine ventricle. Epicardial, M region, and endocardia tissues and cells show distinct, sometimes opposite, responses to a variety of drugs, including those capable of inducing EADs and DADs. Methods and Results: In the present study, we used standard microelectrode techniques to examine the pharmacologic response of these cellular subtypes to therapeutic levels of quinidine and toxic levels of digitalis. Quinidine readily produced prominent EADs and EAD induced triggered activity in tissue preparations from the M region (deep subepicardium), but not in those from epicardium. endocardium, or deep subendocardium of the canine ventricle. Acetylstrophanthidin produced prominent DADs in M cell preparations and subendocardiat Purkinje fibers but only minute DADs, if any, in epicardium, endocardium, or deep subendocardium. DAD-induced triggered activity was observed to arise only in Purkinje and M cells and never in myocardial tissues from the epicardial, endocardial, or deep subendocardial regions of the ventricular wall. Conclusion: We conclude that EADs, DADs, and triggered activity caused by therapeutic levels of quinidine and toxic levels of digitalis are limited to or much more readily induced in a select population of cells in the deep subepicardial (M cell) region of the canine ventricle in addition to the Purkinje system of the heart.     

Distribution of M Cells in the Canine Ventricle

Distribution of M Cells. Introduction: M cells and transitional cells residing in the deep structures of the ventricular free walls are distinguished by the ability of their action potentials to prolong disproportionately to those of other ventricular cells at relatively slow rates. This feature of the M cell due, at least in part, to a smaller contribution of the slowly activating component of the delayed rectifier current (I_ks) is thought to contribute to the unique pharmacologic responsiveness of M cells, making them the primary targets in ventricular myocardium lor agents that cause action potential prolongation and induce early and delayed afterdepolarizations and triggered activity. Previous studies dealt exclusively with the characteristics and distribution of M cells in the canine right and left ventricular free wall near the base of the ventricles. The present study uses standard microelectrode techniques to define their behavior and distribution in the apical region of the ventricular wall as well as in the endocardial structures of the ventricle, including the interventricular septum, papillary muscles, and trabeculae. Methods and Results: Action potentials recorded from the M region (deep subepicardium) displayed similar characteristics (steep action potential duration [APD]-rate relations) in the base and apex. However, important differences were apparent in the other regions. In epicardium. (he spike and dome morphology of the action potential was less accentuated and the rate dependence of APD more pronounced in the apex versus the base. In endocardium, and especially deep subendocardium, rate dependence of APD was considerably more pronounced in the apex. Transmembrane recordings from the subsurface layers of the septum, trabeculae, and papillary muscles revealed M cell behavior (steep APD-rate relations) in the deep subendocardium. Epicardial and transitional behavior were also observed in the deep layers of these endocardial structures. Conclusion: Our results indicate that M cells reside throughout the deep subepicardial layers of the free wall of the canine left ventricle as well as in the deep subendocardiat layers of the septum, papillary muscles, and trabeculae. The data also demonstrate prominent transmural as well as apicobasal gradients of phase I and phase 3 repolarization. These findings may have implications relative to our understanding of the electrocardiographs J wave, T wave, U wave, and long QTV intervals.     

Triggered activity as arrhythmogenic mechanism after myocardial infarction: clinical and electrophysiologic study of one case.

In a woman with an old infarction and sustained ventricular tachycardia, tachycardias were only inducible after short-long RR sequences. After isoprenaline, tachycardias became incessant and all were preceded by short-long RR sequences. This strongly suggests that triggered activity plays a role in initiation of ventricular tachycardias in postinfarction patients.     

Electrophysiologic Characteristics of M Cells in the Canine Left Ventricular Free Wall

Characteristics of M Cells. Introduction: Recent studies have described the existence of M cells in the deep structures of the canine and human ventricle. The present study was designed to further characterize the M cell with respect to its distribution across the canine left ventricular free wall and the dependence of its action potential on [K⁺]₀. Methods and Results: We used standard microelectrode techniques to record transmembrane activity from deep subepicardial or transmural strips isolated from the canine left ventricular free wall near the base as well as subendocardial Purkinje fibers. M cell behavior (steep APD-rate relation) was observed at depths of 1 to 7 mm from the epicardial surface (deep subepicardium to mid-myocardium). M cells were found to be distributed uniformly in the deep subepicardium and did not appear in discrete bundles. We observed transitional behavior throughout the wall. The maximum rate of rise of the action potential upstroke, V_max, increased sharply between epicardium and deep subepicardium (176 ± 13 to 332 ± 61 V/sec), remained high throughout the mid-myocardium and deep subendocardium, and returned to lower values only in the superficial layers of the endocardium (205 ± 21 V/sec). The relationship between V_max and takeoff potential in the M cell was fit by a Boltzmann equation with a V V_0.5 of -68.6 ± 1.5 mV and k of 3.4 ± 0.5. The relationship between resting membrane potential (RMP) and [K⁺]₀ in the M cell was exponential from 8 to 20 mmol/L (58 mV change in RMP per 10-fold change in [K⁺]₀), deviating from K⁺ electrode behavior at [K⁺]₀, < 8 mmol/L. RMP in M cells continued to hyperpolarize at [K⁺]₀ < 2.5 mmol/L, reaching potentials of approximately -110 mV at I⁺]₀, of 1 mmol/L. In contrast, subendocardial Purkinje fibers depolarized at these low levels of [K⁺]₀. Unlike endocardium and epicardium, M cells developed early afterdepolarizations at low [K⁺]₀ and slow rates. Conclusions: Our data indicate that the M cells are widely distributed in the intramural layers of the canine left ventricular free wall. M cells and transitional cells occupy 30% to 40% of the left ventricular wall and an estimated 20% to 40% of the mass of the ventricles of the normal canine heart. They display characteristics common to both myocardial and specialized conducting cells. Like Purkinje fibers, M cells exhibit a relatively large V_max and steep APD-rute relations that are modulated by [K⁺]₀. Unlike Purkinje fibers, M cells do not appear in bundles, they do not depolarize at [K⁺]₀ < 2.5 mmol/L, nor do they exhibit phase 4 depolarization.     

Evidence for the Presence of M Cells in the Guinea Pig Ventricle

M Cells in the Guinea Pig. Introduction: Recent studies have described the presence of M cells in the deep layers of the canine and human ventricle displaying electrophysiologic and pharmacologic features different from those of epicardial (EPI) and endocardial (ENDO) cells. The M cell is distinguished electrophysiologically by the ability of its action potential to prolong disproportionately to that of other myocardial cells with slowing of the stimulation rate and pharmacologically by its unique sensitivity to Class III antiarrhythmic agents. The present study was designed to test the hypothesis that similar cells are present in the guinea pig ventricle. Methods and Results: We used a dermatome to obtain thin strips of left ventricular free wall from the hearts of guinea pigs (8 to 14 weeks old) and standard microelectrode techniques to record transmembrane activity. Action potential duration measured at 90% repolarization (APD₉₀) was significantly longer in mid-myocardial (MID) cells than in surface EPI or ENDO cells at all basic cycle lengths (BCLs) tested. At a BCL of 300 msec, APD₉₀ was 102 ± 21, 136 ± 9, and 95 ± 15 msec in EPI, MID, and ENDO cells (mean ± SD; n = 12). At a BCL of 5000 msec, APD₉₀ was 133 ± 14, 185 ± 24, and 135 ± 13 msec in EPI, MID, and ENDO cells ([K⁺]₀= 4 mM). Thus, APD-rate relations were more pronounced in the MID cells. MID cells were also more sensitive to agents with Class III actions (e.g., d,I-sotalol: 10 to 100 μM), exhibiting a greater APD prolongation than EPI or ENDO. d,I-Sotalol also induced early afterdepolarizations in MID cells hut not in EPI or ENDO cells. The rate of rise of the action potential upstroke (V_max) was significantly greater in MID cells: 129 ± 13, 240 ± 42, and 192 ± 28 V/sec in EPI, MID, and ENDO cells (n = 10 to 18). Conclusion: Our results demonstrate the existence of important transmural electrical heterogeneity in guinea pig ventricular myocardium. The study provides data in support of the existence of M cells in the mid-myocardial layers of the guinea pig ventricle exhibiting longer APDs and a greater sensitivity to agents with Class III antiarrhythmic action.     

溶血磷脂胆碱在缺血性心律失常中的作用

用台氏液加溶血磷脂胆碱（ＬＰＣ）３×１０－４ｍｏｌ／Ｌ灌流离体绵羊心室小梁肌,其０期去极化最大速率（Ｖｍａｘ）、静息电位（ＲＰ）、动作电位幅值（ＡＰＡ）、动作电位复极达ＡＰＡ５０％和ＡＰＡ９０％的时程（ＡＰＤ５０,ＡＰＤ９０）分别下降３９．８％,１０．４％,１４．５％,２１．３％和１４．８％（ｎ＝１２,Ｐ＜０．０１）;用“模拟缺血溶液”和ＬＰＣ３×１０－４ｍｏｌ／Ｌ灌流,其Ｖｍａｘ,ＲＰ,ＡＰＡ,ＡＰＤ５０,ＡＰＤ９０分别下降７８．０％,２２．７％,２６．０％,３５．４％和２１．０％。实验中对“模拟缺血溶液”中各种成分对ＬＰＣ效应的影响进行分析,发现其主要因素是酸中毒。结果表明:ＬＰＣ是心肌缺血中心律失常的重要因素之一,缺血诱导的酸中毒更加重了ＬＰＣ对心肌细胞的毒性作用     

Steroids Prevent Late Extension of Radiofrequency Lesions in the Thigh Muscle of Infant Rats: Implications for Pediatric Ablation

Introduction: Marked late enlargement of radiofrequency (RF) lesions may occur in immature myocardium, suggesting that late proarrhythmic effects may occur in infants and small children undergoing RF ablation. Because late lesion extension may be involved in this phenomenon, we evaluated the impact of corticosteroids on the healing of RF lesions created in the thigh muscle of 29 infant Wistar rats (30 days; 55 g). Methods: Lesion dimensions and histological characteristics were assessed acutely (n = 11), and at 30 days in controls (n = 11, 183 g) and rats (n = 7, 173 g) receiving hydrocortisone after ablation and betametasone for 29 days. Acute (n = 16) and chronic (30 days; n = 5) lesions were also evaluated in adult Wistar rats (300 g). Results: Acutely, lesions in adults and infants were well demarcated from the surrounding tissue. In adults, chronic lesions did not increase in size and were well demarcated histologically. Controls and treated infant rats did not differ with respect to the gross appearance of chronic lesions. Late lesions doubled in size (20 mm in diameter) and were poorly demarcated from the surrounding tissue, exhibiting multiple collagen strands extending from the lesion into normal muscular tissue. In the treatment group, healing was markedly delayed and the extent of collagen proliferation was significantly less than controls. Conclusion: RF lesions created in the thigh muscle of infant rats reveal late enlargement and invasion of normal muscle by intense collagen proliferation. Steroids seem to limit late extension of RF lesions. These findings may have implications for RF ablation procedures in pediatric populations.     

Effects of antiarrhythmic drugs on canine ventricular arrhythmia models: Which electrophysiological characteristics of drugs are related to their effectiveness?

In order to compare and clarify the effects of various antiarrhythmic drugs when given as monotherapy, we reevaluated our previous data on antiarrhythmic drugs and recalculated antiarrhythmic plasma concentrations of drugs for several canine arrhythmia models. We used three spontaneously occurring arrhythmias: a) digitalis-, b) two-stage coronary ligation-, and c) adrenaline-induced arrhythmias. All antiarrhythmic drugs of class I suppressed digitalis arrhythmia, and, except for lidocaine, also suppressed coronary ligation arrhythmia. Class II antiarrhythmic drugs, beta blockers, and class IV antiarrhythmic drugs, Ca antagonists, had common features of effectiveness and suppressed adrenaline arrhythmia in relatively low concentrations. Class III drugs were not effective on these three arrhythmias. Differences among the antiarrhythmic effects of class I drugs could not be explained by their subclassification based either on action potential duration or kinetic properties of dissociation or association with Na channels. New triggered arrhythmia models in vivo and in vitro canine hearts were developed, and drug effects were not the same as those on the three spontaneously occurring arrhythmia models.     

Epinephrine-Induced Ventricular Premature Complexes Due to Early Afterdepolarizations and Effects of Verapamil and Propranolol in a Patient with Congenital Long QT Syndrome

Epinephrine-Induced VPCs and EADs in Congenital LQTS. We report a patient with congenital long QT syndrome in whom early afterdcpolarizations (RAl)s) were demonstrated on monophasic action potential (MAP) recordings in the left ventricular mid-base inferior wall. Epinephrine infusion at 5 fig/mm increased the amplitude of the EADs and the late component of the T(U) wave. Epinephrine also induced ventricular premature complexes (VPCs) with right hundle branch block morphology and left-axis deviation that occurred from the peak of the EADs. Verapamil injection (5 nig) during continuous epinephrine infusion abolished all VPCs with a slight reduction in the amplitude of the EADs. Propranolol injection (5 mg) in addition to verapamil further reduced the amplitude of the EADs and the late component of the T(U) wave. These findings suggest that the epinephrinc-induced VPCs were closely related to triggered rhythm arising from the EADs, and that both verapumil and propranoloi were effective for the suppression of VPCs and EADs.     

Mitral Valve Prolapse and Ventricular Arrhythmias: Observations in a Patient with a 20-Year History

Ventricular Arrhythmias in MVP. Introduction: Ventricular arrhythmias are a common feature in patients with mitral valve prolapse. In an attempt to determine the origin and underlying electrophysiologic mechanism, we describe a patient with ventricular fibrillation, exercise-induced ventricular tachycardia (VT), and, at the time of diagnosis, prolapse of the posterior mitral valve leaflet without mitral regurgitation.
Methods and Results: Treatment with β-blockade and diphenyihydantoin prevented the occurrence of malignant ventricular arrhythmias for more than 17 years. Discontinuation of the therapy resulted in an immediate reappearance of the VT, which, despite the marked enlargement of the left ventricle (secondary to development of severe mitral valve regurgitation), had a strikingly similar morphology. For hemodynamic reasons, the patient was finally selected for valve replacement. Detailed pre-, peri-, and postoperative studies were performed, including administration of flunarizine, body surface mapping, construction of perioperative epicardial and endocardial maps, and studies of the excised muscles in vitro.
Conclusions: Delayed afterdepolarization-induced triggered activity is the mechanism of VT in this mitral valve prolapse patient. The trigger is provided by Isolated ventricular premature complexes elicited by a different electrophysiologic mechanism, possibly reentry, which is related to stretch and presumably to fibrosis of the papillary muscles.     

Treatment of a Patient with an Adenosine-Sensitive Ventricular Tachycardia Using Digoxin

Digitalis and Ventricular Tachycardia. Digoxin was used to treat a patient with an adenosine-sensitive ventricular arrhythmia. The patient had an exercise-induced ventricular tachycardia that was evaluated electrophysiologically and displayed characteristics of a triggered arrhythmia. The tachycardia was terminated reproducibly with 12 mg of intravenous adenosine. After treatment with digoxin (serum level = 1.7 ng/mL), the arrhythmia could no longer be initiated with programmed electrical stimulation or exercise treadmill testing. The patient has since remained symptom free for 10 months. The autonomic effects of digitalis are proposed to mediate drug efficacy in this form of ventricular tachycardia.