Sympathetic activation and heart failure
ABSTRACT Chronic activation of the sympathetic nervous system, via Î²-adrenoreceptor (AR) stimulation, contributes toward progressive heart failure. However, in this regard there are some outstanding issues which require clarity. First, in addition to contributing toward progressive heart failure, it is not clear whether chronic Î²-AR activation can also initiate cardiac decompensation. If so, the mechanisms of this effect also need to be determined. Second, the role of functional variants of Î²-AR genes as determinants of either the development or progression of heart failure requires elucidation. Moreover, whether there is any practical value in genotyping of patients for these variants has yet to be determined. These questions were addressed in the present thesis. With respect to the question of whether chronic Î²-AR activation initiates cardiac decompensation, the mechanisms responsible for the transition from compensated cardiac hypertrophy to heart failure in pressure overload states, such as hypertension, are uncertain. In this thesis I explored whether chronic sympathetic nervous system activation, produced by daily administration of a Î²-AR agonist, could promote the transition to cardiac pump failure in spontaneously hypertensive rats (SHR) with compensated cardiac hypertrophy. After 5 months of daily administration of a Î²-AR agonist, SHR developed marked left ventricular pump dysfunction, whereas normotensive control rats maintained pump function. The pump dysfunction noted in SHR was attributed to marked chamber dilatation with wall thinning, whilst myocardial contractile function appeared to be intact. The changes in cardiac structure and function noted after chronic Î²-AR activation in SHR were similar to those noted in SHR with advanced heart failure. These data provided the first evidence to indicate that chronic Î²- AR activation can promote the transition to decompensated cardiac hypertrophy in pressure overload states, and that this effect is principally mediated by adverse structural remodeling of the cardiac chamber. iii The mechanisms responsible for the effect of chronic Î²-AR activation on cardiac chamber dilatation were subsequently studied. The identified mechanisms included activation of an enzyme that degrades myocardial collagen (matrix metalloproteinase 2) and an increase of myocardial collagen of the type that is susceptible to collagen degradation (non-cross-linked collagen). I also excluded alternative potential mechanisms such as necrosis, apoptosis and an accumulation of type III collagen. However, previous studies have indicated that increases in myocardial collagen concentrations determine myocardial stiffness and not cardiac chamber dilatation. Hence, I performed a study to examine whether the impact of increases in myocardial collagen concentrations on cardiac structure and function depends on the qualitative changes in myocardial collagen. Indeed, using a variety of models of pressure overload hypertrophy associated with increases in myocardial collagen concentrations, I was able to provide evidence to support the theory that increases in myocardial collagen of the cross-linked phenotype will promote myocardial stiffness, whereas increase in myocardial collagen of the non-cross-linked phenotype promotes cardiac dilatation. With respect to the question of whether functional variants of Î²-AR genes contribute toward either the development or progression of heart failure, I studied the role of both functional Î²1-AR and Î²2-AR (together with a Î±2C-AR) gene variants in black South Africans with idiopathic dilated cardiomyopathy (IDC). In a prospective study I obtained data to indicate that the relationship between functional Î²2-AR genotypes and the progression to hospitalization, death or transplantation; a reduced exercise capacity, and left ventricular functional responses to b-blocker therapy, as described by other groups, is unlikely to be attributed to an independent effect of genotype on cardiac chamber dimensions and pump function. Moreover, I was able to show that contrary to what had previously been suggested, genotyping black subjects for functional Î±2C-AR iv and Î²1-AR gene variants is of little use when predicting the development or severity of IDC in this population group.
sympathetic nervous system , heart failure , cellular mechanisms , genetic mechanisms