The response of the left ventricle after large anterior myocardial infarction (MI) is one of remodeling specifically eccentric hypertrophy and cavity dilation, which in turn leads to excess mortality. Remodeling is associated with mechanical dysfunction in noninfarcted regions adjacent to MI. These regions display normal blood flow, no fibrosis and sympathetic denervation. Abnormalities in presynaptic and postsynaptic sympathetic function may interact to contribute to adjacent mechanical dysfunction.
Specific aim number 1 is to determine the nature of defects in the beta-adrenergic receptor cascade in adjacent noninfarcted regions relative to remote regions. In an ovine model of anteroapical MI and LV remodeling, myocardial norepinephrine levels, beta-receptor density, adenylyl cyclase levels and responses to agonists, and G protein coupling will be determined in adjacent and remote regions. Improvement in beta-adrenergic receptor function has been demonstrated with chronic beta-blockade in animal models and humans with LV dysfunction.
Specific aim number 2 is to demonstrate that beta- blockade attenuates defects in the beta-ADR in adjacent noninfarcted myocardium. A set of animals will be randomized to the ACE inhibitor ramipril alone or ramipril plus metoprolol. Beta-blockade when added to ACE inhibition may upregulate beta- receptors, improve adenylyl cyclase response to agonists, and reverse the uncoupling of G proteins in adjacent noninfarcted regions when compared to treatment with ACE inhibitors alone.
Specific aim number 3 is to determine whether improvement in postsynaptic sympathetic function with beta-blockade is associated with improved mechanical function within adjacent noninfarcted regions. Regional mechanical deformation at baseline and with catecholamine stimulation in the two sets of animals (ramipril alone or ramipril plus metoprolol) at 8 weeks post-MI will be measured by MR tagging. Regional mechanical deformation at baseline and with inotropic stimulation will be correlated with regional function of the beta-adrenergic receptor at baseline and in response to beta-agonists. Changes in LV mass, volume, and EF in the two treatment groups will be measured. Effects of beta-blockade on regional cell morphometry, collagen content, and blood flow will be assessed using isolated myocytes, quantitative histopathology, and fluorescent microspheres, respectively.
