ACS: Its Association with Endothelial Dysfunction and Elevated Basal Sympathetic Activity

Acute Coronary Syndrome (ACS) is marked by the rapid onset of symptoms or findings of Unstable Angina (USA), ST-Elevation Myocardial Infarction (STEMI), or Non-ST-Elevation Myocardial Infarction (Non-STEMI) in previously asymptomatic individuals, typically within 24 hours. This is due to a sudden reduction in blood flow to the heart [1]. Endothelial dysfunction plays a crucial role in the pathogenesis of ACS [2]. A healthy endothelium is vital for preventing thrombus formation due to its antithrombotic, antiplatelet, and profibrinolytic properties, while also maintaining vascular tone as required [3]. Endothelial dysfunction is characterized by the endothelium’s loss of these protective functions. Instead, it promotes a pro-thrombotic state, platelet aggregation, and the formation of atheromatous plaques, particularly in individuals with risk factors such as hypertension, diabetes, and smoking [3- 7,8].

The state of endothelium decides normal coronary flow versus endothelial dysfunction and ACS. The precise cause of endothelial dysfunction remains unclear, but several atherosclerosis risk factors [9] have been proposed in prior studies these include- elevated cholesterol levels [10-12], insulin resistance [13,14], hypertension [15], etc. The role of basal sympathetic discharge in endothelial dysfunction is least discussed in the literature therefore its role in precipitating ACS necessitates to be reviewed [8]. Basal sympathetic discharge is primarily controlled by the hypothalamus and is influenced by cortical areas such as the cingulate gyrus and neocortex [7].

Various studies have been reviewed to understand possible mechanisms of the development of ACS including properties and functions of a healthy endothelium, unhealthy endothelium (endothelial dysfunction) basal sympathetic discharge/Sympathetic Skin Response (SSR), and its central connections [1-23].

Properties and functions of the endothelium

Healthy coronary endothelium: Under normal physiological conditions, the endothelium plays a critical role in preventing thrombus formation due to its antithrombotic, antiplatelet, and profibrinolytic properties, while also regulating vascular tone. The endothelium regulates vascular tone by modulating intracellular ATP (Adenosine Tri-Phosphate) production, thus ensuring the dilation of coronary vessels according to demand [8,16-18].

Endothelial dysfunction: Endothelial dysfunction is marked by increased permeability to inflammatory cells, loss of the protective barrier, leukocyte adhesion, thrombosis, and reduced vasodilation and a shift toward a pro-inflammatory and pro-thrombotic state, contributing to the development of atherosclerotic plaques. Further endothelial dysfunction results in ACS [19,20].

Clinical conditions associated with ACS

a) Unstable Angina
b) Non-ST-Elevation Myocardial Infarction (Non-STEMI)
c) ST-Elevation Myocardial Infarction (STEMI)

High basal sympathetic discharge and endothelial dysfunction (possible mechanism)

one important finding is the presence of high basal sympathetic discharge in ACS, also observed in diabetes and hypertension [6-8]. Basal sympathetic discharge refers to the flow of impulses in the sympathetic nervous system at a basal rate. The sympathetic system is continuously active secreting small amounts of epinephrine and norepinephrine at the nerve endings. This baseline discharge is necessary to maintain a normal heart rate, normal blood pressure & vital functions. Normal basal sympathetic discharge is associated with adequate ATP production at the cellular level and endothelium behaves like healthy endothelium. High basal sympathetic discharge results in an ATP mismatch (where inadequate ATP is available to meet the demand at the endothelial cellular level) and endothelium becomes unhealthy i.e. endothelial dysfunction and behaves like prothrombotic and impaired vasodilation and in severe cases results in ACS [8, 21-23].

In the absence of overt discharge, SSR (Sympathetic Skin Response) denotes basal sympathetic discharge. Sympathetic skin response was recorded using standard protocols with the help of Electromyography electrodes placed on the palm and dorsum of the hand. The cold pressor test and isometric hand grip were used as stimulating methods. The response recorded on a computer included latency and amplitude. Latency was calculated from the onset of the stimulus to the beginning of the response. The amplitude was measured from peak to peak [6].
A. Normal response- In normal basal sympathetic discharge, there is a dome-shaped response with long latency and low amplitude [6].
B. In hypertension and ACS high basal discharge i.e. short latency, a high amplitude spike response is observed [6,8].

Central connections and basal sympathetic discharge

Basal sympathetic discharge arises from the hypothalamus, with possible cortical influences. The cerebral cortex has extensive connections with the hypothalamus, which receives afferents from the limbic system (cingulate gyrus), neocortex, and other regions. The hypothalamus sends efferent signals to sympathetic neurons. Thus, the cortex indirectly modulates the sympathetic nervous system [21,23]. The role of the anti-aging gene Sirtuin 1 is important to the prevention of endothelial dysfunction and ACS. Sirtuin 1 is important to the hypothalamus and brain function with relevance to basal sympathetic discharge. Sirtuin 1 activation versus Sirtuin 1 inhibition may be relevant to the reduction in basal sympathetic discharge with relevance to the prevention of ACS [24-26].

Basal sympathetic discharge is normal resting basal sympathetic tone necessary to maintain blood pressure and heart rate. Normal basal discharge is associated with a healthy endothelium. High basal sympathetic discharge is associated with ATP mismatch at the cellular level and leads to endothelial dysfunction and in severe cases ACS. Basal sympathetic discharge originates from the hypothalamus, with possible cortical influences. Reduction in basal sympathetic discharge by managing lifestyle factors i.e. stress, and adequate sleep may help in the prevention of ACS.

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