Factors determining spontaneous ventricular defibrillation

Abstract

Ventricular fibrillation (VF) is defined as a sustained, fatal reentrant arrhythmia that never terminates spontaneously and requires artificial electrical defibrillation. For many years it was believed that spontaneous ventricular defibrillation (SVD) appears only in hearts with small muscle mass that cannot continue fibrillating. SVD appears even in humans, and some drugs transform sustained VF into a transient VF, reverting spontaneously into sinus rhythm. The present criteria for VF were based on the wavelength theory. Accordingly, the persistence of fibrillation depends on the wavelength of the reentrant impulse. Fibrillation can be sustained only if the reentrant circuit is smaller than the length of the refractory tissue. Following this assumption, lengthening of action potential duration (APD) and effective refractory period (ERP) were accepted as factors that determine antiarrhythmic defibrillating ability. The results of recent studies questioned this postulation and clearly showed that prolongation of APD is proarrhythmic. In examining the differences between transient and sustained VF in various mammals, it was hypothesized that SVD requires a high degree of myocardial gap junctional coupling and synchronization. Thus, any compound or condition that enhances intercellular coupling and synchronization or attenuates the dispersion of refractoriness can facilitate SVD. Because one of the main factors involved in intercellular uncoupling is an excess concentration of cytoplasmic free Ca²⁺, it seems plausible that a compound that protects against Ca²⁺ overload and has a positive inotropic effect can serve as a potent defibrillating agent. Evaluation of the anti-arrhythmic properties of various defibrillating compounds showed that a defibrillating drug has the ability to prevent or to attenuate Ca²⁺ overload. By decreasing increased diastolic Ca²⁺ concentration, they enhance intercellular coupling and synchronization, and consequently facilitate SVD, while prolongation of APD or ERP facilitates the appearance of arrhythmias and VF. The novel approach based on upregulation of intercellular coupling to enhance synchronization and on decreased dispersion of refractoriness without prolongation of APD should be taken into consideration in future development of new potent cardioprotective-defibrillating drugs.

Ventricular fibrillation (VF) is one of the major causes of sudden death in humans. Once VF starts the heart ceases to function as a pump and death is imminent unless defibrillation is carried out within a few minutes. Although it was believed that VF cannot terminate spontaneously, evidence suggested that there are two types of VF (1): a sustained VF (SVF) that requires electrical defibrillation and a transient VF (TVF) that spontaneously reverts to a sinus rhythm. The latter was observed in various small animals such as rats, guinea pigs and rabbits. TVF found in rodent was described as an intrinsic phenomenon of the small heart that has not enough muscle mass for sustaining the fibrillating process (1,2). In contrast, SVF appeared in some animals with small hearts such as pigeons (3) and older rodents (4), while TVF was seen in some larger hearts such as those of cats (4), very young dogs (5) and even humans (6).

It is now clear that TVF in humans is not so rare and that some compounds facilitate spontaneous termination of VF in experimental (4,5,7–13) and clinical conditions (14,15).

MECHANISMS INVOLVED IN SVF AND TVF

Bacaner in 1966–8 showed that pretreatment with bretylium tosylate transforms SVF into TVF in dogs (9) and humans (14). Although bretylium has sympathomimetic effects, increases myocardial catecholamine concentrations (16) and is positively inotropic (17), Bkaily et al (18) related its defibrillating action to the fibrillation threshold and to K⁺ channel blocking, ie, to a class III effect.

K⁺ channel blocking compounds prolong action potential duration (APD) as well as effective refractory period (ERP) (19,20), and the hypothesis explaining their class III antiar-rhythmic effects was based in principle on wavelength (WL) theory (21–23). This theory was developed in the search for the mechanisms underlying atrial tachycardia and fibrillation. The main factors involved in initiating and sustaining atrial fibrilloflutter were considered to be structural and functional. From the structural point of view, structural inhomogeneities (24,25) resulting in dispersion of electro-physiological properties such as refractory period (26), repolarization (27), excitability (28), differences in conductivity and unidirectional block (28) (which permit subsequent reentry of the returning activation wave front) were thought to be classical requirements of reentry. From the functional point of view, initiation and maintenance of reentrant arrhythmias were believed to depend on a critical relation between conduction velocity (CV) and tissue refractoriness (ie, ERP) (21,29,30). Atrial fibrilloflutter is closely related to the WL of the reentrant impulse given by the product of ERP and CV, ie, WL = ERP × CV (21,22). The stability of reentrant circuits depends on the relation of the WL to the length of the reentrant pathway (21,23). Early studies on arrhythmias caused by circuit movement postulated that reentry is possible only if WL is shorter than the length of the reentrant pathway (31).

Following this assumption, verified by a computer model (32), conversion of atrial fibrilloflutter to sinus rhythm and the prevention of initiation of atrial fibrilloflutter have been correlated with spontaneous or pharmacologically induced prolongation of APD, refractory period and WL (33). Smeets et al (23) suggested that, together with the mass of cardiac tissue and the degree of inhomogeneity of conduction properties, the length of the excitation wave seems to be a key factor in the inducibility and sustaining of fibrillation.

Although the mathematical (22) and computer models (32), and many experimental and clinical studies showed a causal correlation between ERP and CV, antiarrhythmic properties and reduced probability of cardiac arrhythmias (34), many reports questioned this assumption. Moreover, it is well known that in many cases prolongation of APD and ERP support the initiation and the continuity of VF.

NOVEL APPROACH BASED ON CELL TO CELL COUPLING AND SYNCHRONIZATION

Results obtained in mammals of both sexes, of various species and of different ages indicate that spontaneous termination of VF (self-defibrillation) is a normal feature in young mammalian heart and that it decreases with age (4,5,35). TVF exhibits a coarse, slow rate and quite synchronized electrical fibrillating activity, with much of the ventricular mass acting in synchrony, while SVF exhibits fine, unorganized, less synchronized electrical activity at higher rate, with small local fibrillating areas (36). VF starts as an organized electrical activity of low frequency, resembling TVF, which in a few seconds becomes faster, less organized and unsynchronized (37), most likely by spontaneous wave front brakes that continuously regenerate daughter wavelets (38).

A comparison of SVF with TVF in the same animal species and under the same experimental conditions found no differences in cardiac muscle mass, heart rate and APD between animals that exhibited TVF and those that exhibited SVF (4,5,14,39). Synchronized fibrillation occurs in hearts with functional cell to cell coupling, ensuring continuous propagation of electrical signals throughout the myocardium, causing the cardiomyocytes to act in synchrony (4,35,39–43). Abnormal coupling in aged (44), hypertrophic (45) and hypokalemic (46) hearts deteriorates intermyocyte communication, resulting in conduction and synchronization disturbances. Preservation or enhancement of coupling can facilitate conversion of SVF to TVF by decreasing the number of reentry circles through synchronization of small local circles into bigger ones. Thus, spontaneous defibrillation can occur when the viable myocardium acts as a functional syncytium, and the majority of myocardial cells are simultaneously in the refractory period (5,35,41).

Intermyocyte communication through gap junctions is a dynamic process, known to be modulated by intracellular Ca²⁺ and H⁺ ions as well as by various endogenous and exogenous compounds, such as cAMP and cGMP (47). Therefore, myocardial alterations in the concentration of these mediators might affect intermyocyte electrical coupling. Remodelling of the heart of various origins is associated with decreased or abnormal intermyocyte coupling, which predisposes to fractionated conduction (48), disturbances in synchronization and arrhythmogenesis (49–52). The degree of spatial and transmural heterogeneity of electrical alterations that are linked with metabolic and structural heterogeneity might determine the appearance of SVF (53,54).

The finding that TVF is a normal feature in young mammals (5,9,35) can be explained in that the myocardium of young mammals is more resistant to Ca²⁺ overload and metabolic acidosis (which decrease coupling [44]), is predominately under sympathetic autonomic regulation (which enhances coupling), and has a high number of gap junctions (4,5). On the contrary, hearts of older mammals (or diseased hearts) are characterized by suppression of the Ca²⁺ homeostatic systems (55–57), by decreased intercellular connections and by more fragile intermyocyte coupling (49), as well as by predominately vagal autonomic regulation or decreased response to catecholamines (58). Accordingly, hearts of older mammals have a lower capacity to prevent Ca²⁺ overload (59) and to maintain adequate functional cell to cell communication. These conditions, rather than muscle mass, may explain the transient nature of reentrant arrhythmias in young animals and sustained arrhythmias in older mammals (4,5,40).

Degeneration of TVF into SVF is probably determined by critical suppression of intermyocyte coupling due to a rapid myocardial cell activity-related increase in cytoplasmic free Ca²⁺ concentration ([Ca²⁺]_i) (unpublished data) and hypoxia (60,61). Fast cellular activity (60) and hypoxia or ischemia are known to increase junctional resistance (62,63), decrease gap junctional conduction and cause intermyocyte uncoupling (64), most likely due to an increase in [Ca²⁺]_i (49,65), intracellular acidosis (66,67) or alterations in the intracellular cAMP:cGMP ratio (68). VF and hypoxia cause the function of the ion homeostatic system (Na⁺/K⁺-ATPase and Ca²⁺-ATPase) to deteriorate, and activate the Na⁺/Ca²⁺ exchanger in a reverse mode, which can contribute to Ca²⁺ overload, increased Ca²⁺ oscillations and changes in Ca²⁺ handling (69). Excessive diastolic [Ca²⁺]_i downregulates the gap junctional channels and decreases intercellular coupling (65), most likely due to increased junctional and internal longitudinal resistance (70), and is closely related to an increase in resting tension. All of these conditions (64,71) favour VF-induced deterioration of myocardial intermyocyte synchronization and increase the number of fibrillating microareas, which supports the persistence of VF and decreases the heart’s self-ventricular defibrillating ability.

SVF can be terminated either by electrical shock (72,73) or by pharmacological facilitation of myocardial synchronization (12,14,74,75) through upregulation of gap junctional coupling (76–78). VF-induced Ca²⁺ overload can even lead to failed electrical defibrillation and postshock reinitiation of VF (79). It can be expected, therefore, that prevention or attenuation of VF-related harmful effects on cell to cell coupling is an important prerequisite for self-ventricular defibrillation. Following this assumption, we hypothesized (80) that any defibrillating drug should slow down the fibrillation rate, enhance or reestablish intercellular coupling and prevent intercellular electrical uncoupling, most probably by increasing the intracellular concentration of cAMP, decreasing elevated [Ca²⁺]_i or preventing Ca²⁺ overload.

To test these assumptions we examined in a series of experiments (75,76,81,82) the effect of adrenaline, cAMP, tricyclic antidepressants, phenotiazines, class III drugs (d-sotalol and tedisamil) and procainamide on intercellular myocardial coupling and synchronization, as well as on the ultrastructural integrity of the intercellular junctions and [Ca²⁺]_i in cell culture.

All of these drugs were found to decrease previously increased [Ca²⁺]_i toward its basal level, while their administration in normal external Ca²⁺ had no effect on [Ca²⁺]_i. Moreover, in some cases pretreatment prevented Ca²⁺ overload, maintained normal [Ca²⁺]_i, and prevented high [Ca²⁺]_i-induced uncoupling and desynchronization (83).

We suggest, therefore, that class III agents increase the concentration of cAMP, consequently increasing sarcolemmal Ca²⁺ influx, while preventing increased diastolic Ca²⁺ by accelerating its uptake by sarcoplasmic reticulum. These effects can lead to an increase in Ca²⁺ transients and positive inotropic effect, as well as to a net decrease in [Ca²⁺]_i (83–85). Result that we (86) and Parmley et al (87) have obtained support the assumption that tedisamil and d-sotalol increase cAMP; moreover, recent experiments (88) proved that these antiarrhythmic or defibrillating compounds decrease [Ca²⁺]_i and prevent Ca²⁺ overload by increasing sarcoplasmic reticular reuptake of Ca²⁺.

The cardioprotective defibrillating ability of the tested compounds is most likely due to their sympathomimetic effects, ie, cAMP-related enhancement of Ca²⁺ uptake by the sarcoplasmic reticulum and cAMP-related enhancement of gap junctional conduction. Consequently, intermyocyte coupling, communication and synchronization are protected. These effects enable the viable myocardium to act as a syncytium to prevent spontaneous breakup of reentering wavelets and to prevent the continuity of reentry and fibrillation.

CONCLUSIONS

We suggest that all of the examined compounds possess a defibrillating ability by increasing sarcoplasmic reticular uptake of Ca²⁺ and by preventing downregulation of intermyocyte coupling. This effect is unrelated to their influence on APD or membrane stabilization. Class I compounds (tricyclic antidepressants, phenothiazines and procainamide) facilitate self-defibrillation, although they decrease maximal velocity, and by decreasing CV can support continuation of the fibrillating process. Class III compounds (d-sotalol and tedisamil) transform SVF into TVF although they prolong APD and ERP, a feature that has arrhythmogenic properties that can lead to sudden cardiac death. These compounds exhibited an apparent antiarrhythmic-defibrillating ability in a dosage that prevented Ca²⁺ overload but before decreasing maximal velocity or prolonging the QT interval corrected for heart rate. The same results were found in patients who were given sotalol (89).

Acceptance of our hypothesis that the defibrillating effect is closely related to protection of intermyocyte coupling and synchronization, and development of positive inotropic drugs that prevent Ca²⁺ overload and cell to cell uncoupling, and that lack arrhythmogenic effects such as prolongation of APD or QT interval, or decreased maximal velocity, may lead to more potent and safe antiarrhythmic defibrillating treatment, which clinics have needed for a long time.