Autonomic function and ventricular tachyarrhythmias during acute myocardial infarction

INTRODUCTION

Sudden cardiac death is a major health-related problem worldwide, accounting for more than half of cardiovascular mortality[1]. It is invariably caused by sustained ventricular tachyarrhythmias (VTs), occurring in the setting of acute myocardial infarction (MI). The high incidence and the ominous prognosis of ischemia-related VTs dictate ample research efforts toward in-depth understanding of the underlying mechanisms, aiming at the advent of preventive strategies[2].

During acute-MI, epinephrine is released in the ischemic myocardium, followed by activation of chromaffin cells in the adrenal medulla[3]; epinephrine, either locally released or circulating, alters ventricular electrophysiology and has been long known to exert a prominent role in genesis of VTs[4]. Acute-MI is also often accompanied by marked autonomic dysfunction, but its precise timecourse along the acute phase of MI and the ensuing arrhythmogenic effects remain incompletely understood.This article briefly summarizes recent knowledge on this topic that may offer further insights into the complex pathophysiology of sudden cardiac death.

总之，将法律认同作为实现“一带一路”倡议的基础性工作，这要求我国在充分研究和尊重现有国际商事规则的基础上，提出既适合中国国情，又适应世界发展潮流的现代商事规则。只有在充分考虑国际社会可接受程度的基础上，完善我国的商事法律制度并对外推广才能真正在推动法律趋同的过程中获得法律认同。因此，在“一带一路”倡议中向世界推行的商事规则，不可能等到我国商事规则完善之后才进行，我国应当双管齐下，在现代商法理念的指导下构建与完善国内商事法律制度的同时，积极探寻符合世界商事活动要求的商事规则，从而确保我国“一带一路”倡议的准确方向和最终目标的实现，提升我国在当代世界商事规则形成上的话语权。

AUTONOMIC DYSFUNCTION DURING MI

Afferent stimuli

Although cardiogenic reflexes were first recognized in the mid-19th century, studies on the autonomic effects on the ischemic myocardium and their impact on VTs were systematically performed only a century later[5]. These led to early clinical reports introducing the role of autonomic dysfunction on ventricular electrophysiology following acute coronary occlusion[6]. The activation of ventricular afferent fibers in the ischemic myocardium was subsequently demonstrated, mediated by hemodynamic changes induced by acute-MI, as well as by the local production of chemical stimuli[7]. This process is dynamic, determined by the timecourse of left ventricular hemodynamics and by the balance between the rate of production and metabolism of various mediators.

饲养管理工作开展的科学性是决定猪养殖成效的关键因素之一[2]，为尽量将猪高热综合征对养猪业及具体养殖场的影响降到最小，应充分重视饲养管理工作。相关养殖人员应结合以下几点内容做到科学饲养管理：首先，养殖场应坚持自繁自养原则，实行封闭式管理。有效预防病毒通过外部因素进入猪群中，养殖人员只要保证猪养殖环境内不存在危险因素即可。其次，养殖场应在原有基础上对饲养管理条件进行改善。圈舍的通风、防暑、消毒、驱虫等工作展开的都会对猪高热综合征的发病率产生一定的影响，因此，相关养殖单位必须从养殖场的建设做起，提升各项设备设施的质量，从根本上做好饲养管理工作。

In response to acute coronary occlusion, two temporally distinct peaks have been described in various species, with several lines of epidemiological data pointing towards a similar curve in man[1,2]. Although this topic has been long debated, classification into VTs linked to reversible ischemia versus those occurring during evolving necrosis is based on firm pathophysiologic differences; more importantly,classification into early and delayed VTs is clinically sound,as it corresponds to the pre- and in-hospital phases,respectively, carrying profound consequences on survival rates and potential treatment strategies. As noted above, scarce data exist in humans on the incidence of early-phase VTs and concurrent autonomic responses.Therefore, the investigation on the underlying mechanisms of ischemia-induced VTs relies largely on in vivo animal models; indeed, these models offer clear-cut advantages in monitoring physiologic parameters during specific periods after coronary ligation, in the absence of the confounding effects of various interventions.

在电网规划中应用新能源，有集中接入形式、分布接入形式、分散接入形式等，由于新能源具有波动性以及随机性特征，因此，会对电网潮流分布形式产生一定的影响。另外，在电网运行中，电压、载流等也会对电网潮流产生较大影响。通过将随机波动、规模大，并且分布形式的新能源应用于电网规划中，也会使电网潮流注入功率出现多元化特征，同时，电网中有功分布规律以及无功分布规律复杂程度不断增加，这样就会对电网损耗的调控、统计等带来较大压力。

Efferent autonomic activation

The effects of the autonomic nervous system on ventricular electrophysiology during myocardial ischemia have attracted rigorous research efforts[11-14]: Sympathetic activation shortens the ventricular action potential and the refractory period under normal conditions, but these actions vary in the ischemic ventricular myocardium. Thus,in addition to ionic imbalance, sympathetic activation enhances the dispersion of repolarization across the energy-depleted ischemic myocardium and lowers the fibrillation-threshold[11], perhaps without altering local conduction[12]. By contrast, parasympathetic stimulation prolongs the action potential duration and the effective refractory period[13]; hence, vagal activation exerts potent anti-fibrillatory actions on the ischemic myocardium,although transmural dispersion of repolarization seems unaffected[14].

Afferent stimuli reach the nucleus tractus solitarius, which acts as an integrative center, signaling emergency changes in the central nervous system. In this structure, a series of sensory nuclei, embedded in the medulla oblongata, form circuits with other nuclei in the brainstem and with a large number of other central regions. The medulla contains sympathetic cell bodies, with respective nerves travelling along the spinal cord; from there, sympathetic fibers synapse with sympathetic ganglia, and postganglionic fibers ultimately synapse at their target sites. The parasympathetic cell bodies exit the medulla as long preganglionic efferent fibers that form synapses with postganglionic fibers within the myocardium.

Early clinical reports have underscored the involvement of both arms of the autonomic nervous system post-MI[15];however, the precise time-course of sympathetic and vagal alterations and their contribution to arrhythmogenesis remain incompletely understood[2]. This can be explained by the marked individual variation, attributed to the size and location of MI, its hemodynamic sequelae, and to the magnitude of the accompanying symptoms of pain and anxiety. Moreover, accurate pathophysiologic conclusions are hindered by the inevitable delays in monitoring patients in coronary care units, coupled with the confounding effects of treatment.

VTs during acute MI

Sympathetic afferents are mainly nonmyelinated,with only occasional thinly myelinated Aδ-fibers, that form a network over the epicardium[8]. Most sympathetic afferents are activated by adenosine triphosphate and are classified as ischemia-sensitive[7], although the pathophysiologic significance of those not responding to adenosine triphosphate remains unknown. Afferent activation depends on the location of the ischemic myocardium, as shown by experimental[9] and clinical[10]data; in this regard, vagal Aδ- and nonmyelinated C-fibers,located in the inferior left and right ventricular wall, are frequently activated during ischemia involving these walls.

ANALYSIS OF RECENT EXPERIMENTAL STUDIES

Our group recently examined the autonomic responses and the incidence of VTs in the in vivo rat-model, by comparing sham-operated controls with an animal-group post-ligation of the left coronary artery[16]. Continuous electrocardiographic recording was performed in conscious rats via implanted telemetry transmitters, and autonomic indices were derived by heart rate variability techniques; specifically, sympathetic activity was assessed by detrended fluctuation analysis, and vagal activity by time- and frequency-domain analysis. Frequent VTs were observed post-ligation, following the typical pattern of an early prominent peak and a more prolonged delayed arrhythmogenic window. Vagal activity decreased markedly immediately post-ligation and remained low throughout the 24 h-observational period. The pattern of sympathetic activation differed, showing a progressive rise; it became significant at a later stage post-MI and remained elevated until the end of the recording. Using micro-neurographic recordings, such delayed sympathetic activation post-MI was also observed by Jardine et al[17] in the ovine-model, in which enhanced cardiac sympathetic nerve-activity was observed only after the first hour post-ligation. These findings support the notion of attenuated parasympathetic, rather than enhanced sympathetic-inputs, contributing to early-phase VTs, given the aforementioned anti-fibrillatory vagal effects on the ischemic myocardium[14].

Two recent studies lend further support to this hypothesis: in the canine-model[18], no antiarrhythmic effect was found after suppression of the left stellateganglion for 60 min post-MI, except from experiments in which its action was completely abrogated. Likewise, a study from our group[19] examined the incidence of VTs post-ligation in rats pretreated with clonidine, a centrally acting inhibitor of sympathetic preganglionic-neurons;treated rats displayed a lower incidence of VTs occurring during the delayed phase post-MI, but early phase arrhythmogenesis was unaffected[19].

PERSPECTIVE

Autonomic dysfunction, commonly observed during acute MI, contributes to the genesis of VTs. Autonomic responses vary, depending on several modulating factors, some of which remain incompletely understood; hence, the precise nature and time-course of such responses during the acute phase of MI is subject of continuous investigation.Early-stage VTs are at the center of research-efforts,because they invariably occur prior to medical attendance and they are responsible for most cases of sudden cardiac death. Recent in vivo experimental studies have drawn the attention toward vagal withdrawal, associated with profibrillatory effects in the ischemic ventricular myocardium.Such decreased parasympathetic inputs appear to occur swiftly in response to ischemia, whereas sympathetic activation is more gradual and coincides with a second cluster of VTs. These studies provide further insights into the pathophysiology of acute MI and sudden cardiac death. Nonetheless, these findings should be viewed as hypothesis-generating research that warrants further validation in animal models and, ultimately, in patients.The investigation of autonomic dysfunction during acute MI is an intriguing topic of high clinical importance that may unravel further aspects of the interrelation between the brain and the heart.

REFERENCES

1 Kolettis TM. Ventricular arrhythmias during acute ischemia/infarction: mechanisms and management. In: Kibos AS, Knight BP,Essebag V, Fishberger SB, Slevin M, Tintoiu IC, editors. Cardiac arrhythmias: from basic mechanism to state-of-the-art management.London: Springer-Verlag 2014: 237-251 [DOI: 10.10007/978-1-4471-5316-0_18]

2 Kolettis TM. Coronary artery disease and ventricular tachyarrhythmia:pathophysiology and treatment. Curr Opin Pharmacol 2013; 13:210-217 [PMID: 23357129 DOI: 10.1016/j.coph.2013.01.001]

3 Schömig A. Adrenergic mechanisms in myocardial infarction: cardiac and systemic catecholamine release. J Cardiovasc Pharmacol 1988; 12 Suppl 1: S1-S7 [PMID: 2468829 DOI: 10.1097/00005344-198806121-00002]

4 Warner MR, Kroeker TS, Zipes DP. Sympathetic stimulation and norepinephrine infusion modulate extracellular potassium concentration during acute myocardial ischemia. Circ Res 1992; 71:1078-1087 [PMID: 1394871 DOI: 10.1161/01.RES.71.5.1078]

5 Han J, Garciadejalon P, Moe GK. Adrenergic effects on ventricular vulnerability. Circ Res 1964; 14: 516-524 [PMID: 14169970 DOI:10.1161/01.RES.14.6.516]

6 Webb SW, Adgey AA, Pantridge JF. Autonomic disturbance at onset of acute myocardial infarction. Br Med J 1972; 3: 89-92 [PMID:4402759 DOI: 10.1136/bmj.3.5818.89]

7 Ardell JL. Sensory transduction of the ischemic myocardium. Am J Physiol Heart Circ Physiol 2010; 299: H1753-H1754 [PMID:20952672 DOI: 10.1152/ajpheart.01009.2010]

8 Fu LW, Longhurst JC. Regulation of cardiac afferent excitability in ischemia. In: Canning BJ, Spina D, editors. Sensory Nerves. Berlin,Heidelberg: Springer Berlin Heidelberg 2009: 185-225 [DOI: 10.1007/978-3-540-79090-7_6]

9 Zucker IH, Cornish KG. The Bezold-Jarisch in the conscious dog.Circ Res 1981; 49: 940-948 [PMID: 6115723 DOI: 10.1161/01.RES.49.4.940]

10 Chiladakis JA, Patsouras N, Manolis AS. The Bezold-Jarisch reflex in acute inferior myocardial infarction: clinical and sympathovagal spectral correlates. Clin Cardiol 2003; 26: 323-328 [PMID: 12862298 DOI: 10.1002/clc.4950260706]

11 Opthof T, Coronel R, Vermeulen JT, Verberne HJ, van Capelle FJ,Janse MJ. Dispersion of refractoriness in normal and ischaemic canine ventricle: effects of sympathetic stimulation. Cardiovasc Res 1993; 27:1954-1960 [PMID: 8287403 DOI: 10.1093/cvr/27.11.1954]

12 Kolettis TM, Kontonika M, La Rocca V, Vlahos AP, Baltogiannis GG, Kyriakides ZS. Local conduction during acute myocardial infarction in rats: Interplay between central sympathetic activation and endothelin. J Arrhythm 2017; 33: 144-146 [PMID: 28416983 DOI:10.1016/j.joa.2016.07.010]

13 Ng GA, Brack KE, Coote JH. Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart--a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation. Exp Physiol 2001; 86: 319-329 [PMID:11471534 DOI: 10.1113/eph8602146]

14 Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res 2014; 114: 1004-1021[PMID: 24625726 DOI: 10.1161/CIRCRESAHA.113.302549]

15 Lombardi F, Sandrone G, Spinnler MT, Torzillo D, Lavezzaro GC,Brusca A, Malliani A. Heart rate variability in the early hours of an acute myocardial infarction. Am J Cardiol 1996; 77: 1037-1044[PMID: 8644654 DOI: 10.1016/S0002-9149(96)00127-0]

16 Kolettis TM, Kontonika M, Lekkas P, Vlahos AP, Baltogiannis GG, Gatzoulis KA, Chrousos GP. Autonomic responses during acute myocardial infarction in the rat model: implications for arrhythmogenesis. J Basic Clin Physiol Pharmacol 2018; 29: 339-345[PMID: 29634485 DOI: 10.1515/jbcpp-2017-0202]

17 Jardine DL, Charles CJ, Ashton RK, Bennett SI, Whitehead M,Frampton CM, Nicholls MG. Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model.J Physiol 2005; 565: 325-333 [PMID: 15774526 DOI: 10.1113/jphysiol.2004.082198]

18 Yu L, Wang M, Hu D, Huang B, Zhou L, Zhou X, Wang Z, Wang S, Jiang H. Blocking the Nav1.8 channel in the left stellate ganglion suppresses ventricular arrhythmia induced by acute ischemia in a canine model. Sci Rep 2017; 7: 534 [PMID: 28373696 DOI: 10.1038/s41598-017-00642-6]

19 Kolettis TM, Kontonika M, Barka E, Daskalopoulos EP,Baltogiannis GG, Tourmousoglou C, Papalois A, Kyriakides ZS.Central sympathetic activation and arrhythmogenesis during acute myocardial infarction: modulating effects of endothelin-B receptors.Front Cardiovasc Med 2015; 2: 6 [PMID: 26664878 DOI: 10.3389/fcvm.2015.00006]