Link of Endothelin System and Ischemia-Induced Ventricular Tachyarrhythmias: History
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Contributor:
Eleni-Taxiarchia Mouchtouri
,
Thomas Konstantinou
,
Panagiotis Lekkas
,
Theofilos M. Kolettis

Sympathetic activation has long been known to play a key role in the pathophysiology of ischemia-induced arrhythmias, but the regulating factors remain under investigation. The endothelin system is implicated as an important modulator of sympathetic activation in the setting of acute coronary syndromes. This system consists of a family of three endothelin isopeptides (ET-1, ET-2, and ET-3), produced by numerous cell types, and two specific receptors (ETA and ETB) that are widely expressed throughout the body. Endothelin is synthesized and released continuously, but it is also stored in intracellular endothelial storage pools and secreted by exocytosis. The main source of circulating endothelin in the setting of acute coronary syndromes appears to be the ischemic myocardium, with plasma levels correlating with the incidence of VTs. In addition to its vasoconstrictive effects in the coronary circulation, endothelin is implicated in ischemia-induced arrhythmogenesis, both directly and indirectly, the latter mode exerted by modulating sympathetic responses.

  • myocardial ischemia
  • ventricular tachyarrhythmias
  • sympathetic activation
  • endothelin

1. Sympathetic Activation during Myocardial Ischemia

Sympathetic activation in response to acute coronary occlusion has been long recognized as an important contributor to arrhythmogenesis. Following an immediate exocytotic phase, norepinephrine is released from sympathetic nerve terminals in the ischemic myocardium via non-exocytotic mechanisms, with such local release demonstrated in isolated, ex vivo beating preparations [1]. In the in vivo setting, ischemia-induced sympathetic activation entails more complex responses that involve the entire sympatho-adrenal axis. Catecholamines are secreted from chromaffin cells in the adrenal medulla, whereas efferent discharges from the brain stem stimulate myocardial sympathetic nerve endings globally in the heart [2]. Understanding the complex sympathetic activation during acute coronary syndromes is important, based on the spatial variations associated with each arm. More specifically, the effects of circulating and neurally mediated norepinephrine differ, as circulating catecholamines can only reach myocardial sites with adequate perfusion, in contrast to local release that occurs in the synaptic cleft of ischemic areas [3].
Sympathetic activation elicits positive inotropic effects that serve the maintenance of cardiac output but creates a highly arrhythmogenic milieu in the ventricular myocardium. Studies in conscious large-animal models [4] and patients [5] have demonstrated the precedence of VTs by enhanced sympathetic activity, supporting epidemiologic data in patients with acute coronary syndromes complicated by early-phase VTs [6].
Sympathetic activation participates in the genesis of VTs via several mechanisms [7]. It raises the cardiomyocyte resting membrane potential, thereby enhancing automaticity, and induces delayed afterdepolarizations that can lead to triggered activity; ectopic rhythms are sustained by the dispersion of ventricular repolarization that forms areas with inhomogeneous local electrophysiologic properties [8]. The latter mechanism prevails in the setting of myocardial ischemia, due to its opposite actions on the repolarization of the non-ischemic versus the ischemic myocardium, consisting of shortening versus prolongation, respectively [9]. As a result, spatial differences in excitability are enhanced, particularly at the rim of the ischemic zone, thereby creating functional substrates for reentrant circuits.

2. The Endothelin System during Acute Coronary Syndromes

2.1. Direct Effects

Endothelin exerts arrhythmogenic effects in isolated ventricular cardiomyocytes, consisting of enhanced automaticity and early afterdepolarizations [10]. Several cellular mechanisms underlying these actions have been proposed, such as enhanced calcium release from the sarcoplasmic reticulum (acting via inositol trisphosphate receptors), inhibition of delayed rectifier potassium current, or activation of the Na+/H+ exchanger [11]. Moreover, endothelin may impair the gap junctional coupling of cardiomyocytes, thereby contributing to anisotropic conduction [12]. The latter mechanism has been demonstrated in cellular electrophysiologic studies, but its importance during acute myocardial ischemia is unclear. Of note, preliminary in vivo experiments by a group lend support to these findings, after the analysis of local activation in the ventricular myocardium, by means of multi-electrode array recordings [13]. Based on the potential importance of this mechanism, further investigation is required on the effects of the endothelin system on electrical conduction in the ischemic myocardium.

2.2. Indirect Effects

In addition to the direct arrhythmogenic properties of endothelin, several lines of evidence have demonstrated a complex interplay between the endothelin system and sympathetic activation [14]. This is present at the adrenal gland level and at the ventricular myocardial level, with endothelin receptors exerting opposing effects [15].

2.3. ETA and ETB Receptors in the Adrenal Gland

The role of endogenous endothelin in catecholamine secretion in response to electrical stimulation was first investigated in isolated, perfused adrenal glands of rats [16]; in these experiments, selective ETA-receptor blockade inhibited catecholamine output, whereas pre-treatment with selective ETB-receptor blockade abolished this response.
The significance of these findings on arrhythmogenesis during acute coronary syndromes is uncertain. Utilizing the adrenalectomy and ETB-deficient rat models, a group examined the contribution of the adrenal medulla on ischemia-induced VTs and the modulatory effects exerted by the endothelin system [17]. Contrasting delayed VTs, it found evidence that circulating catecholamines represent only a minor contribution to early-phase arrhythmogenesis, with functioning ETB receptors in the ventricular myocardium exerting protective effects.

2.4. Endothelin Receptors in the Myocardium

The presence of both endothelin receptors in cardiac sympathetic nerve varicosities were first demonstrated in guinea pig hearts and subsequently in other species, including man [18]. In healthy hearts, the endothelin system interferes with exocytotic norepinephrine release, with the ETA-mediated inhibition of norepinephrine re-uptake exceeding the ETB-receptor-mediated attenuation of norepinephrine release [19]. The endothelin system plays a prominent role also in non-exocytotic norepinephrine release during myocardial ischemia.

3. Central Autonomic Network

3.1. Brain Endothelin System

The factors regulating the central autonomic network during myocardial ischemia are complex and remain incompletely understood. In addition to adrenal and myocardial sites, there is growing evidence that the endothelin system also modulates central autonomic inputs, based on its wide distribution in the brain and spinal cord of experimental animals [20] and humans [21]. Indeed, early studies have described potent hemodynamic changes after intracisternal endothelin administration [22]. Although initially attributed to cerebrovascular effects, the non-vascular location pattern of endothelin receptors in the brain points towards neuromodulatory actions [23], which are likely mediated by alterations in calcium influx and neuronal conduction [24].
Anatomical and functional studies have provided further support to the concept of central autonomic control exerted by the brain endothelin system [25]. For example, tyrosine hydroxylase activity measurements have demonstrated the interaction between the endothelin and the olfactory system [26]. Moreover, functional studies using cellular c-fos expression showed the activation of the brainstem after intracerebroventricular endothelin administration, an action mediated by ETA receptors [27]. Lastly, cardiac sympathetic responses were modulated after exogenous endothelin administration in the paraventricular nucleus in rats; these effects were dose-dependent and were prevented by pretreatment with ETA-receptor blockade [28].

3.2. Brain Endothelin System during Myocardial Ischemia

To further assess the role of the brain endothelin system during myocardial ischemia, scholars examined the effects of intracerebroventricular ETA-receptor blockade in rats [29]; this protocol targets the endogenous endothelin system and avoids the confounding effects of exogenous endothelin administration. Scholars reported beneficial effects on delayed arrhythmogenesis post-coronary ligation, whereas infarct size was unchanged. Scholars subsequently extended the observation period to include both early and delayed arrhythmogenic phases post-coronary occlusion [30]. It found decreased sympathetic activity, evidenced by noninvasive indices derived from heart rate variability analysis, with an improved autonomic function associated with a lower incidence of VTs during both phases.

3.3. Brain Endothelin System and Vagal Activity

In addition to the sympathetic component, there is now sufficient evidence to suggest that autonomic modulation by the endothelin system also encompasses vagal responses. Early studies have demonstrated the presence of endothelin receptors in the dorsal vagal complex of the brainstem [31], with vagal activation elicited after intracisternal endothelin administration [32]. These findings were subsequently confirmed after selective endothelin microinjections into the dorsal vagal complex of anesthetized rats; this intervention modulated gastric motor, arterial blood pressure, and heart rate, with such effects mediated via ETA receptors [33]. These findings are in keeping with the aforementioned study [34], reporting a moderately enhanced vagal activity after intracerebroventricular ETA-receptor blockade.

4. Acute Emotional Stress and Arrhythmogenesis during Myocardial Ischemia

Acute emotional stress evokes complex autonomic responses, displaying distinct features from those elicited during physical exertion [35]. A considerable amount of evidence suggests that the endothelin system is also implicated in autonomic responses during emotional stress. In rats, acute psychosocial stress increases plasma endothelin levels [36] and lowers vagal activity [37]. Remarkably, similar findings were reported in response to acute emotional excitement in healthy subjects and in patients with previous myocardial infarction [38]. The origin of circulating endothelin in such cases has been debated, but the vascular endothelium appears to be the most likely cellular source [39].
The implications of these observations on ischemia-induced VTs are poorly defined. Irrespective of the possible causative link between acute emotional stress and coronary artery disease, this clinical setting is common in contemporary society. An example (perhaps in extremis) is given by the high incidence of VTs among patients with implanted defibrillators following the World Trade Center terrorist attack in 2001 [40]. Furthermore, a cohort study [41], examining patients admitted with acute coronary syndrome after intense excitement, reported profoundly increased endothelin (and inflammatory markers, such as monocyte chemoattractant protein-1) when compared to either a reference group or to healthy controls.
Examined collectively, current evidence suggests a pathophysiologic role of the endothelin system in acute coronary syndromes associated with acute emotional stress, but the possible ramifications on early-phase arrhythmogenesis warrant further investigation.

5. Conclusions

Early-phase VTs in the setting of acute coronary syndromes often lead to sudden cardiac death and remain an important health-related problem worldwide. Myocardial ischemia induces major changes that favor the onset of VTs via all known arrhythmogenic mechanisms. This milieu is further altered by sympathetic activation, consisting of local and systemic catecholamine release, each with a distinct electrophysiologic impact. The endothelin system augments both processes via ETA receptors, whereas ETB receptors in the myocardium ameliorate local early-phase sympathetic activation and arrhythmogenesis.
Acute coronary syndromes are often accompanied by autonomic dysfunction that contributes to VTs, but the underlying pathophysiology is complex and incompletely understood. The role of the brain endothelin system in modulating sympathetic and vagal activity has recently emerged, particularly in cases of acute emotional stress preceding myocardial ischemia. The interaction between the endothelin system and the autonomic nervous system is currently under investigation, with a view towards implementing therapeutic strategies that will lower the incidence of sudden cardiac death.

This entry is adapted from the peer-reviewed paper 10.3390/life12101627

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