ABSTRACT
Chronic activation of the sympathetic nervous system, via β-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 β-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 β-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 β-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 β-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 β-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 β-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 β-
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.
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The mechanisms responsible for the effect of chronic β-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 β-AR genes
contribute toward either the development or progression of heart failure, I studied the
role of both functional β1-AR and β2-AR (together with a α2C-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 β2-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 α2C-AR
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and β1-AR gene variants is of little use when predicting the development or severity of
IDC in this population group.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/4521 |
| Date | 05 March 2008 |
| Creators | Badenhorst, Danelle |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Format | 64650 bytes, 3549304 bytes, application/pdf, application/pdf, application/pdf, application/pdf |
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