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

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.