Surgical therapies for heart failure have been proposed based on a geometric reconfiguration of ventricular structure. Early generations of these interventions, however, have failed to account for complexities of myocardial biology, and have not realized their anticipated clinical potential. To optimize clinical benefit, strategies for surgical ventricular reconstruction may need to account for physiologic and pathologic changes in myocyte function at the cellular level. Chronic, progressive cardiac dysfunction after a left ventricular (LV) infarct is associated with an apoptotic loss of cardiomyocytes in, and with thinning and fibrosis of, the remote uninfarcted myocardium. Recurrence of ventricular dilatation has also been found to limit the long-term benefit derived in some models of ventricular reconstruction. It is hypothesized that these remodeling changes in the post-Mi ventricular wall are determined, at least in part, by the balance between different memebers of the mitogen activated protein kinase (MARK) family. Specifically, it is postulated that a reduction in cardiac myocyte (CM) extracellular signaling-related kinase 1/2 (ERK1/2) activation, particularly relative to that of p38-MAPK, will result in a further increase in CM apoptosis and worsening of post-Mi remodeling. Conversely, it is also hypothesized that an increase in ERK1/2 activity, known to inhibit myocyte apoptosis and to stimulate physiologic, but not pathologic, cardiac hypertrophy in normal hearts, will reduce the pathologic deterioration seen in chronic Ml. To test these hypotheses, a mouse model of chronic coronary ligation will be performed in both a double knockout mouse essentially devoid of alpha-1 adrenergic receptors that are largely responsible for ERK 1/2 activation in CM, and in transgenic mice that overexpress a constitutively active form of the ERK-activator MAPK/ERK kinase 1 (aMEK1) in a myocardial-specific fashion. This loss and gain of ERK activity will be correlated to cardiomyocyte apoptosis, and to progressive changes in LV structure, measured grossly and histologically, and function, measured via in situ echocardiography and ex vivo Langendorff preparation. Finally, we will test the hypothesis that combining surgical therapy with clinically relevant, therapeutic upregulation of ERK activation, achieved either through pharmacologic stimulation of alpha-1 adrenergic receptors or through myocardial aMEK1 gene transfer, will preserve and enhance the long-term benefit derived from mechanical ventricular reconstruction.
