How Abnormal Sympatho-Activation Can Potentially Develop Heart Failure: A Mini Review

Cardiac sympathetic afferent that signal the sensation of cardiac pain, ostensibly, has more underlying mechanisms than what scientists have ever been led to believe. Cardiac sympathetic afferent reflex, also known as (CSAR), has been shown to be responsive to a variety of stimuli. Many of which scientists observed in increased levels during ischemia hydrogen ion, oxygen radicals, potassium, lactate, ATP, prostaglandins bradykinin, substance p and, finally and most importantly, endogenous substances (neurohormones) such as norepinephrine (NE). In the outset of chronic heart failure (HF), it has been known for a long time, that there are abnormalities in arterial baroreceptor input which depress its sensitivity, and arterial chemoreceptors seem augmented. Therefore, they tend to not only initiate sympathetic outflow but also to sensitise cardiac afferents which are appearing to do the same thing where there are abnormalities in vagus mechano-reflexes as well. Some of these receptors are in the spinal reticulate tract and interestingly these a third pathways give off neurons to the brainstem some in the hypothalamus and trance translate through the thalamus and then ultimately up into the cortex where we have sensation of pain. Here in this essay, we aim to discuss important aspects of cardiac failure in relation to abnormal sympatho-activators through evaluation of different available studies and animal models.

Interaction between Endothelin-1 and Left Stellate Ganglion Activation: A Potential Mechanism of Malignant Ventricular Arrhythmia during Myocardial Ischemia

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control, n=6) and ET-1 into the LSG (n=6) were included. The ventricular effective refractory period (ERP), LSG function, and LSG activity were measured at different time points. VA was continuously recorded for 1 h after left anterior descending occlusion (LADO), and LSG tissues were then collected for molecular detection. Compared to that of the control group, local ET-1 microinjection significantly decreased the ERP and increased the occurrence of VA. In addition, local microinjection of ET-1 increased the function and activity of the LSG in the normal and ischemic hearts. The expression levels of proinflammatory cytokines and the protein expression of c-fos and nerve growth factor (NGF) in the LSG were also increased. More importantly, endothelin A receptor (ETA-R) expression was found in the LSG, and its signaling was significantly activated in the ET-1 group. LSG activation induced by local ET-1 microinjection aggravates LADO-induced VA. Activated ETA-R signaling and the upregulation of proinflammatory cytokines in the LSG may be responsible for these effects.

Angiotensin-(1-7) in Paraventricular Nucleus Contributes to the Enhanced Cardiac Sympathetic Afferent Reflex and Sympathetic Activity in Chronic Heart Failure Rats

Background/Aims: Cardiac sympathetic afferent reflex (CSAR) enhancement contributes to exaggerated sympathetic activation in chronic heart failure (CHF). The current study aimed to investigate the roles of angiotensin (Ang)-(1-7) in CSAR modulation and sympathetic activation and Ang-(1-7) signaling pathway in paraventricular nucleus of CHF rats. Methods: CHF was induced by coronary artery ligation. Responses of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to epicardial application of capsaicin were used to evaluate CSAR in rats with anesthesia. Results: Ang-(1-7) increased RSNA, MAP, CSAR activity, cAMP level, NAD(P)H oxidase activity and superoxide anion level more significantly in CHF than in sham-operated rats, while Mas receptor antagonist A-779 had the opposite effects. Moreover, Ang-(1-7) augmented effects of Ang II in CHF rats. The effects of Ang-(1-7) were blocked by A-779, adenylyl cyclase inhibitor SQ22536, protein kinase A inhibitor Rp-cAMP, superoxide anion scavenger tempol and NAD(P)H oxidase inhibitor apocynin. Mas and AT1 receptor protein expressions, Ang-(1-7) and Ang II levels in CHF increased. Conclusions: These results indicate that Ang-(1-7) in paraventricular nucleus enhances CSAR and sympathetic output not only by exerting its own effects but also by augmenting the effects of Ang II through Mas receptor in CHF. Endogenous Ang-(1-7)/Mas receptor activity contributes to CSAR enhancement and sympathetic activation in CHF, and NAD(P)H oxidase-derived superoxide anions and the cAMP-PKA signaling pathway are involved in mediating the effects of Ang-(1-7) in CHF.