Ventricular remodeling in chronic heart failure (CHF) often occurs following myocardial infarction (MI), yet the natural history remains unpredictable due to the chronicity of the process and therapeutic interventions involved. Ventricular remodeling is a dynamic process encompassing anatomical changes (ventricular dilation, cardiomegaly, wall thinning), functional changes (increased reliance on Frank-Starling mechanisms), and cellular/molecular alterations (cytoskeletal remodeling, shifts in arterio-venous electrolyte balances).
This study encompassed three major phases: 1) Development of an ovine model of CHF to serve as an experimental platform; 2) Implantation of a left ventricular assist device (LVAD) in the CHF animals to investigate the role of acute ventricular unloading on myocardial oxygen consumption (LVVO2) and arterio-venous electrolyte balances as a therapy for CHF; 3) Investigations into the temporal and spatial alterations of the cytoskeletal protein desmin and its relationship to the ventricular remodeling cascade.
Sheep underwent microembolization of the circumflex coronary artery until left ventricular ejection fraction (EF) decreased to <35%. In a subgroup of CHF sheep carried out to four months, these animals then underwent LVAD implantation to assess the affects of partial ventricular unloading on LVVO2 and arterio-venous electrolyte balances. The results of this phase of our study found that partial LVAD support of as little as 25% significantly reduces LVVO2 and restores proper electrolyte gradients in CHF through comparatively minor reductions in cardiac work. A second group was documented via echocardiography for up to 24 months (mean 17 months). EF decreased from 51±3% (baseline) to 25±2% (month four) (p<0.05) and stabilized through month 24 (23±5%, p<0.05), while LV end-systolic area (LVESA), and LV end-diastolic area (LVEDA) increased by 222% and 98%, respectively, through month 24.
To investigate the role of regional stimuli and determine whether remodeling processes are differentially regulated or evolve in concert with each other, we mapped the temporal and spatial distribution of intracellular (desmin content), extracellular (fibrosis content), and cellular (myocyte hypertrophy) remodeling in our ovine model of CHF and found that these remodeling processes dissociate from each other during the progression of CHF and are heterogeneously distributed in response regional stressors.