Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers

Table 1 Cardiovascular reflexes and their pathophysiological implications in heart failure

Type of neurally-mediated cardiovascular reflex	Proposed mechanism of action	Pathophysiological consequence in heart failure
Arterial baroreceptor reflexes	In HF acts as a response to perceived reduction in stroke volume or diastolic blood pressure; It is implicated that reduced carotid sinus and aortic arch afferent nerve firing as a response to systolic stretch disinhibits efferent sympathetic discharge; This reflex is impaired in terms of heart rate control, however, efferent sympathetic nerve activity might be preserved in human HF, even in advance stage	↓ Reduced reflex vagal response; ↓ reduced heart rate variability; ↑ increased cardiac NE spillover; ←→no change in renal NE spillover; ↑mean sympathetic discharge to peripheral muscles is increased
Cardiac chemosensitive reflexes	Myocardial ischemia and reperfusion elicits increased sympathoexcitatory response by chemically (reactive oxygen species) stimulating sympathetic afferent fibers in both anterior and infero-posterior regions of the left ventricle; Platelet activation and local release of serotonin (5-HT) through a 5HT3 receptor mechanism and regional changes in pH from lactic acid stimulate sympathetic afferents in myocardium; Cardiac sympathetic afferent reflex is enhanced in HF and acts in the positive-feedback fashion	↑ Increased shift and predominance of sympathetic efferent discharge; ↓ parasympathetic depletion; ↑ sympathetic activation; ↑ increased blood pressure; ↑ adverse left-ventricular remodeling; ↑ increased propensity for malignant arrhythmias and sudden cardiac death
Cardiopulmonary mechanosensitive reflexes	Normally elicited by the stretch of unmyelinated afferents sensitive to mechanical input, located intracardially and within pulmonary veins; It is implicated that impairement of this reflex decreases efferent sympathoinhibition to periphery; Cardiac-specific myelinated afferent are responsible for observed sympathoexcitatory effects characterized by the increased local cardiac NE spillover due to increased filling pressures (e.g. ↑ high LA pressure); Bezold-Jarisch reflex – mediated by nonmyelinated vagal afferent pathways – acts in sympathoinhibitory fashion and promotes reflex bradycardia, vasodilation and hypotension	↓ Reduced cardiopulmonary reflex regulation of central sympathetic outflow to peripheral tissues (dominantly skeletal muscles); ↑ paradoxical excitation and increase in sympathetic outflow in the setting of high LA pressure
Cardio-cardiac reflexes	Coronary occlusion elicits the activity of preganglionic fibers in left thoracic sympathetic ramus communicans (T3) and increases discharge towards heart via efferent sympathetic innervation	↑ Increased myocardial oxygen consumption; ↑ facilitation of malignant arrhythmias; ←→ might also have a protective effect in sense that they augment contractility, therefore, opposing ventricular dilatation and/or impending cardiogenic shock
Peripheral and central chemoreceptor reflexes	These receptors monitor partial pressures of oxygen and CO2 within arterial vessels and close to heart and escalate afferent sensory discharge according to changes; Peripheral chemoreceptors – dominantly respond to hypoxia; Central chemoreceptors – dominantly respond to hypercapnia; Peripheral and central receptor chemosensitivity is significantly increased in HF and is linked to augmented MSNA	↑ Increased ventilation; ↑ increased sympathetic outflow; ↑ increased heart rate and systolic blood pressure; ↓ suppressed inhibition of sympathetic outflow that is mediated by arterial baroreflexes; ↑ increased peripheral and central chemoreflex-mediated sympathoexcitation is linked to poor 4-yr survival in HF patients
Pulmonary stretch receptor reflex	Fast and shallow breathing (high respiratory rate and low tidal volume) decreases stimulation of sympathoinhibitory reflex that is initated with lung stretch; HF patients with such breathing had increased MSNA burst frequency or amplitude; There is a correlation between decrease in resting tidal volume and attenuated sympathoinhibitory effect of lung inflation reflex with increased sympathoexcitation	↓ Decreased the resting tidal volume; ↓ attenuated sympathoinhibitory effect of lung inflation reflex
Reflexes originating from skeletal muscles	Autonomic responses of skeletal muscles during exercise are modulated by skeletal ergo-receptors in order to optimize muscle work; HF patients had augmented afferent reflexes originating from skeletal muscles	↑ Increase in the efferent ventilatory and sympathoneural responses to exercise

HF: Heart failure; LA: Left atrium; MSNA: Muscle sympathetic nerve activity; NE: Norepinephrine.

Table 2 Selected biomarkers in respect to their pathophysiological effects, cellular mechanisms, circulating levels and outcomes in heart failure

	NE	NPY	GAL	ET-1	CST
Pathophysiological effects in heart failure or cardiovascular diseases	↑ Promotes cardiac hypertrophy; ↑ promotes induction of fetal genes in myocardial remodeling; ↑ mediates and enhances apoptosis of cardiac myocytes in vitro; ↑ promotes arterial vasoconstriction; ↑ promotes tachyphylaxis; ↑ increased cardiac and renal spillover in HF; ↓ impaired oxygen utilization and exercise efficiency in patients with stable HF; ↑ increased sympathetic nerve activity and reduced clearance of norepinephrine	↑ Vasoconstriction; ↑ promotes adverse cardiac remodeling; ↑ increased cardiac spillover; ↑ promotes angiogenesis; ↑ associated with increased platelet aggregation and adhesion following thrombosis; ↑ stimulates atherosclerosis; ↑ promotes vasoconstriction of coronary microvasculature; ↑ enhancing the NE-mediated effect of sympathetic discharge, associated with the increased incidence of ventricular arrhythmia; ↑ enhances inhibition of vagally-mediated ;bradycardia through Y2 receptors; ↑ potentiates arrhyhtmias following STEMI, despite beta-blocker therapy	↓ Reduces cardiac cholinergic neurotransmission; ↓ reduces acetylcholine biovailability in the synapse junctions; ↓ reduces vagally-mediated bradycardia; ↑promotes antithrombotic phenotype on endocardial endothelial cells; ↑ increased cardioprotective activity against ischemia-reperfusion injury in H9C2 cardiomyoblasts in vitro	↑ Promotes vasoconstriction (most potent vasoconstrictor in humans); ↑ promotes vascular and cardiac hypertrophy; ↓ decreases NE reuptake thus propagating adrenergic effects; ↓ reduces coronary flow; ↑ promotes inotropic and chronotropic responses in cardiomyocytes; ↑ promotes mitogenic actions; ↑ activation of endothelin-dependent pathways is observed in HF; ↑ correlates with hemodynamic impairment and severity of pulmonary hypertension in HF; ↑ promotes angiogenesis	↓ Decreases arterial blood pressure (direct and indirect vasodilation); ↓ inhibits catecholamine release; ↓ decreases NPY and ATP release; ↓ attenuates cardiac inotropy and chronotropy; ↑ promotes angiogenesis; ↓ blunts atherosclerosis; ↓ reduces inflammation; ↓ reduces thrombogenicity; ↑ promotes VSMC proliferation; ↓ decreases arrhytmogenic events; ↓ decreases ventricular remodeling
Cellular mechanism	Activation of α and β adrenergic receptors (G protein-coupled)	Activation of G protein-coupled post-synaptic Y1-Y6 receptors (Y2 is also pre-synaptic) on sympathetic nerve endings	Activation of G protein-coupled receptors – GAL1R, GAL2R, GAL3R	Activation of endothelin A (ETA) and B (ETB) receptors(both G protein-coupled)	Acts on neuronal nicotinic acetylcholine receptor (nAchR)
Circulating levels in HF vs controls	↑ Circulating plasma levels;↑ urinary excreted levels	↑ Circulating plasma levels	←→ Not significantly different plasma levels	↑ Plasma levels;↑ renal tissue levels	↑ Circulating plasma levels
Association with mortality and morbidity in HF	↑ High NE levels were associated with significantly increased mortality and morbidity in patients with congestive HF; ↑ circulating NE levels positively correlate with HF syndrome severity	↑ Elevated levels in coronary sinus were associated with composite endpoint of VAD implantation, death, and cardiac transplant among patients with stable chronic HF undergoing CRT implantation	Not established (no studies available)	↑ Increased ET-1 levels associated with higher HF syndrome severity;↑ increased ET-1 levels associated with mortality in HF	↑ Increased CST levels were independently associated with all-cause and cardiac mortality in patients with chronic HF; ↑ correlates with NYHA functional class

NE: Norepinephrine; NPY: Neuropeptide Y; GAL: Galanin; ET-1: Endothelin; CST: Catestatin; CRT: Cardiac resynchronization therapy; FU: Follow-up; HF: Heart failure; NYHA: New York Heart Association; STEMI: ST-elevation myocardial infarction; VAD: Ventricular assist device; VSMC: Vascular smooth muscle cell.