Heart failure is a chronic syndrome in

Heart failure is a chronic syndrome in which the heart is unable of pumping an adequate supply of blood to meet the metabolic requirements of the body or generating the required elevated ventricular filling pressures to maintain output [34]. Despite considerable advances in the treatment of heart failure, such a disease still represents a severe social and clinical burden [42], [79], [80]. The TAK-715 is best viewed as a complex dynamic system, continually adapting to optimize organ perfusion. During heart failure, diverse neurohormonal mechanisms are triggered to maintain cardiac output [4]. Heart failure is considered a progressive disease that begins long before signs or symptoms become clinically evident: initially there is a complex adaptive neurohormonal activation – required to compensate for cardiac dysfunction – which includes nervous system, renin-angiotensin-aldosterone system, endothelin, natriuretic peptides, and vasopressin. The process progressively becomes maladaptive, leading to increased mechanical stress on the failing heart and causing harmful electrical and structural events [81], [82], [83]. Thus, β-blockers, Angiotensin II AT1 receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists represent cornerstones for the treatment of patients with heart failure. Given the decreased myocardial contractility observed in heart failure and the positive inotropic response obtained with βAR agonists, it was initially attractive to attempt to overcome the βAR desensitization in order to ameliorate cardiac function via the stimulation of the adrenergic system [84]. Several authors also provided experimental evidence that β2AR overexpression might have been a new treatment for heart failure [85], [86]. Other investigators demonstrated that the overexpression of β1AR [87] or β2AR [88] leads to cardiomyopathy and heart failure, as reflected by decreased cardiac function, increased fibrosis, cardiomyocyte apoptosis, and overall mortality. The central part of the adrenal gland, called adrenal medulla, is the main source of catecholamines and is comprised of groups of adrenergic and noradrenergic chromaffin cells and, to a lesser extent, ganglionic neurons [42], [89]. The adrenal gland can be seen as a specialized sympathetic ganglion, receiving inputs from the sympathetic nervous system via pre-ganglionic fibers. Yet, the adrenal gland directly secretes neurohormones into the bloodstream [89]. The sympathetic overdrive observed in heart failure correlates with a higher risk of arrhythmias and left ventricular dysfunction [90]. Moreover, augmented levels of catecholamines can cause myocardial damage via enhanced cardiac oxygen demand and by increasing peroxidative metabolism [91] and ultimately leading to structural alterations, including focal necrosis and inflammation, increased collagen deposition, and interstitial fibrosis [92], [93], [94]. Systemically circulating or locally released catecholamines trigger two main classes of ARs: α1AR and β2AR, causing vasoconstriction and vasodilatation, respectively [46], [47], [95]. With aging, such a fine equilibrium is progressively shifted toward increased vasoconstriction, most likely due to a defective vasodilatation in response to βAR stimulation. Increased basal levels of circulating catecholamines have been observed both in heart failure and with advancing age, mirrored by a decrease in the number of high-affinity βARs. These findings suggest that these alterations might be attributable to βAR desensitization rather than an actual reduction in βAR density [10], [21], [96]. Both expression and activity of GRK2 increase in vascular tissue with aging [97]. Equally important, an impairment in βAR-mediated vasorelaxation has been observed in hypertensive patients [31] and in animal models of hypertension [75], [97]: such an alteration has been related to increased GRK2 abundance and activity. Transgenic overexpression of GRK2 in the vasculature impairs βAR signaling and the vasodilatative response, eliciting a hypertensive phenotype in rodents. This aspect has been confirmed in humans: GRK2 expression correlates with blood pressure and impaired βAR-mediated adenylyl-cyclase activity [97]. Additionally, variants of the gene encoding for β2AR have been associated with longevity [10].