Booysen, Hendrik Le Roux2012-07-122012-07-122012-07-12http://hdl.handle.net/10539/11679M.Sc. (Med.)--Faculty of Health Sciences, University of the Witwatersrand, 2011In-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.enAdrenergic Beta Receptor BlockadesHeart Failure, Congestive|xtherapyThesis