M.Sc. (Med.)--Faculty of Health Sciences, University of the Witwatersrand, 2011 / In-part through a decrease in cardiac cavity dimensions (reverse
remodelling), β-adrenergic receptor blockers have been demonstrated to produce
marked benefits to morbidity and mortality in patients with chronic heart failure.
However, maximum doses of these agents are often difficult to achieve in patients
with chronic heart failure because of the negative inotropic, hypotensive and other
side effects. Whether blockade of the excessive adrenergic effects achieves
complete reverse remodelling in progressive heart failure is nevertheless uncertain.
To test this hypothesis I simulated the adverse effects of chronic adrenergic
stimulation on the heart by administering daily doses of the β-adrenergic receptor
agonist, isoproterenol (ISO) (2.42 X 10-8 mmol.kg-1) to rats for 6 months and
compared left ventricular (LV) dimensions and systolic function to Saline-vehicle
treated rats. To imitate the effects of complete adrenergic receptor blockade
following the development of adrenergic-induced adverse cardiac changes, I
similarly administered ISO for 6 months and then subsequently withdrew the daily
ISO administration for a further 4 months (ISO+Recovery) before comparing left
ventricular dimensions and function to Saline+Recovery treated rats.
In comparison to a Saline vehicle-treated group, after 6 months of ISO
administration, LV end diastolic and systolic diameters, and the volume intercept of
the left ventricular diastolic pressure-volume relationship (LV V0), were markedly
increased and LV endocardial fractional shortening (FSend), LV end systolic chamber
(slope of the systolic pressure-volume relationship-Ees) and myocardial (slope of the
systolic stress-strain relationship-En) contractility were substantially decreased. The
extent of the adverse remodelling produced by chronic ISO administration was
exemplified by the 2.5 times increase in LV V0 (ISO=0.40±0.04 vs Saline=0.16±0.01,
p<0.001), a change proportionate to that noted in humans with chronic heart failure.
iii
The proportion of ISO-treated rats with LV chamber diameters, and LV V0 values
above the 95% confidence interval for Saline-treated rats was markedly greater than
the proportion of Saline-treated rats above their own 95% confidence intervals.
Moreover, the proportion of ISO-treated rats with FSend, LV Ees and LV En values
below the 95% confidence interval for Saline-treated rats was markedly greater than
the proportion of Saline-treated rats below their own 95% confidence intervals.
Following a 6 month period of ISO administration and a subsequent period of
withdrawal of ISO administration for a further 4 months, LV chamber diameters, LV
V0, FSend, LV Ees and LV En were all noted to be similar to age-matched
Saline+Recovery control rats. Indeed, the increases in LV V0 observed after 6
months of ISO administration were completely reversed (ISO+Recovery=0.21±0.02
vs Saline=0.23±0.02, p<0.001). The proportion of ISO+Recovery rats with LV
chamber diameters, and LV V0 values above the 95% confidence interval for the
Saline+Recovery rats was similar to the proportion of Saline+Recovery rats above
their own 95% confidence intervals. Moreover, the proportion of ISO+Recovery rats
with FSend, LV Ees and LV En values below the 95% confidence interval for
Saline+Recovery rats was similar to the proportion of Saline+Recovery rats below
their own 95% confidence intervals. Chronic ISO administration and the withdrawal
of ISO administration was not associated with changes in myocardial necrosis
(pathological score and myocardial collagen concentrations).
In conclusion, marked cardiac dilatation and pump dysfunction produced by
chronic β-adrenergic receptor activation can be completely reversed by withdrawal of
the excessive adrenergic stimulus. These data highlight the importance in chronic
heart failure of achieving complete blockade of the pathways activated by excessive
β-adrenergic receptor stimulation even in individuals with advanced cardiac
dilatation.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/11679 |
| Date | 12 July 2012 |
| Creators | Booysen, Hendrik Le Roux |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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