Adrenergic System, Physical Exercise, and ED in HFrEF Patients

The sympathetic nervous system’s (SNS) over activity in heart failure is a well-established mechanism that has a transitional contribution to the pathophysiology, is supportive of cardiac function initially, and is a burden on it ultimately [52]. Research has revealed molecular alterations occurring in SNS in different models, myocardial cells, peripheral lymphocytes, and endothelial cells. Interpretation of these changes should take into consideration genetic polymorphism in human adrenergic receptors (ARs) and NOS enzymes, which adds to the complexity of the pathophysiological interactions of these phenomena in heart failure.

In the myocardium, the most abundant AR are βAR subtypes. Their density changes from a predominant β1AR (77%): β2AR (23%) in a non-failing heart to 60%: 38% with improper signaling mechanisms in a failing heart [53,54]. βAR desensitization has also been reported in the myocardium of heart failure patients [55,56], a property that has also been associated with receptor phosphorylation by adrenergic receptor kinase-2 [57]. Peripheral blood lymphocytes served as another model to study changes in βAR in heart failure patients. This is because they exist in high numbers in Tsuppressor/cytotoxic cells, B cells, natural killer cells, and monocytes [58]. These numbers have been found to correlate with βAR density in human myocardial cells [59]. In heart failure patients, the density of βAR on peripheral lymphocytes and isoproterenol-stimulated adenylate cyclase activity were reduced [60].

The benefits of physical exercise in heart failure were studied on myocardial cells and peripheral lymphocytes. In animal models, physical exercise increased myocardial βAR density and reduced G-protein-coupled receptor kinase-2 over-expression, with the resultant improvement of cardiac inotropic activity in response to adrenergic stimulation [61]. In patients with heart failure, physical exercise has increased the density of βAR in peripheral lymphocytes [60]. The third studied model are endothelial cells (ECs), where all AR subtypes exist (with β2AR sub-type predominance) and directly or via NOS stimulation induce NO-dependent vasodilatation [62,63]. α2AR are also expressed and involved in the activation of NOS and NO-dependent vasodilatation [64].

The benefits of physical exercise in heart failure were studied on myocardial cells and peripheral lymphocytes. In animal models, physical exercise increased myocardial βAR density and reduced G-protein-coupled receptor kinase-2 over-expression, with the resultant improvement of cardiac inotropic activity in response to adrenergic stimulation [61]. In patients with heart failure, physical exercise has increased the density of βAR in peripheral lymphocytes [60]. The third studied model are endothelial cells (ECs), where all AR subtypes exist (with β2AR sub-type predominance) and directly or via NOS stimulation induce NO-dependent vasodilatation [62,63]. α2AR are also expressed and involved in the activation of NOS and NO-dependent vasodilatation [64].

Considering the current findings, we could anticipate that physical exercise in heart failure might modify the molecular changes to the adrenergic system at the EC level and improve endothelial function, as it does enhance autonomic receptor-mediated endothelium-dependent vasodilatation in animal models [65]. Such a benefit might be in addition to its ability to recruit EPCs from the bone marrow to repair endothelial function. Therefore, future studies should establish which exercise regimens should be emphasized and to which heart failure patients. In addition, more research is needed to establish the effect of physical exercise on prognosis if continued or terminated.