Heart failure associated with reduced systolic function or congestion (or both) is characterized by substantial neuro-hormonal activation in heart, kidney and skeletal muscle [
23,
46]. These neurohumoral responses include activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system, further aggravating heart failure by increasing ventricular afterload and preload. Initial measures of serum noradrenaline verified an inverse relation between serum levels and mortality, which was initially hypothesized to be a hormonal marker of hemodynamic stress, and later with the appreciation of the value of beta blockers to improve morbidity and mortality in heart failure, felt to itself be a mediator of the increased mortality rates [
47,
48]. Moreover, renal noradrenaline spillover is an independent predictor of heart transplant free survival; patients with elevated serum norepinephrine experience rates of mortality three times higher in untreated than treated heart failure patients [
2,
23,
49]. Renal sympathetic efferent traffic can underlie congestion due to frequency dependent release of renin, sodium retention in the proximal tubules and elevation of renal vascular resistance [
2]. Renin release, and subsequent generation of local angiotensin II directly stimulates proximal tubular sodium reabsorption by activating sodium bicarbonate co-transporters and sodium hydrogen exchange [
50] and also by causing vasoconstriction of the efferent renal arteriole, lowering peritubular hydrostatic pressure [
51]. Aldosterone, acting within the distal tubule and collecting duct, up-regulates and activates the basolateral Na/K pumps retaining remaining intraluminal Na. The clinical importance of the sympathetically mediated impact on fluid retention is evident even after standing, which increases renal sympathetic efferent signaling in heart failure and hepato renal syndrome [
2]. Upright posture alone decreases eGFR and raises plasma concentrations of noradrenaline, renin and aldosterone in both hepato renal and heart failure patients [
52]. The effects of chronic activation of efferent renal signaling on total body Na and water balance are likely critical in edema and congestion formation. The natriuretic peptides are considered markers of volume expansion, however, they may also serve as indicators of excess renal efferent signaling [
53]. The natriuretic actions of natriuretic peptides are reduced in heart failure. Thematically, the family of natriuretic peptides may represent compensation to the anti natriuretic consequences of renal sympathetic activity and other activated vasoconstrictor systems. Experimental ligation of renal nerves protects against development of postprandial natriuretic resistance and the development of congestion or rises in ventricular filling pressures [
54]. The therapeutic value of renal denervation in heart failure was evaluated in a similar experimental model of coronary ligation induced myocardial infarction in rats [
55]. This study, in which renal denervation was performed pre-onset of myocardial infarction, demonstrated reduced ventricular filling pressure and improved ventricular function compared to non-denervated controls [
55]. More recently, evidence from a rabbit model with pacing induced heart failure demonstrated that the reduction in renal blood flow and the increase in renal vascular resistance can be prevented by surgical renal denervation, indicating that renal sympathetic nerve activity elicits a detrimental effect on renal blood flow [
56]. Equally important in this later study, expression of angiotensin receptors was found to be dependent on sympathetic innervation [
57]. Beyond renal management of volume, the appreciation that circulating blood volume can abruptly be altered by neurologically recruiting splanchnic venous storage blood pools suggests that increased central sympathetic drive has potential to both increase total body salt and water through renal mechanisms as well as abruptly change circulating volume by recruiting splanchnic venous stores of blood [
2]. This neurogenic mechanism may explain the often clinically frustrating finding in patients who experience dramatic increases in dyspnea and pulmonary congestion in the absence of either weight changes or abnormalities of ventricular function, i.e. sympathetically mediated changes in circulating volume.