Revascularization of Chronic Hibernating Myocardium Stimulates Myocyte Proliferation and Partially Reverses Chronic Adaptations to Ischemia

Abstract

Background The time course and extent of recovery after revascularization of viable dysfunctional myocardium is variable. While fibrosis is a major determinant, myocyte structural and molecular remodeling may also play important roles. Objective This study sought to determine whether persistent myocyte loss and/or irreversibility of protein changes that develop in hibernating myocardium have an impact on functional recovery in the absence of infarction. Methods Swine instrumented with a chronic left anterior descending artery (LAD) stenosis to produce hibernating myocardium underwent percutaneous revascularization with serial functional recovery evaluated for 1 month (n = 12). Myocardial tissue was evaluated to assess myocyte size, nuclear density, and proliferation indexes in comparison to normal animals and nonrevascularized controls. Proteomic analysis by 2-dimensional differential in-gel electrophoresis (2D-DIGE) was used to determine the reversibility of molecular adaptations of hibernating myocytes. Results At 3 months, physiological features of hibernating myocardium were confirmed, with depressed LAD wall thickening and no significant infarction. Revascularization normalized LAD flow reserve, with no immediate change in LAD wall thickening. Regional LAD wall thickening slowly improved, but remained depressed 1 month post-percutaneous coronary intervention (PCI). Surprisingly, revascularization was associated with histological evidence of myocytes reentering the growth phase of the cell cycle and increased cKit+ cells. Myocyte nuclear density returned to normal, while regional myocyte hypertrophy regressed. Proteomic analysis demonstrated heterogeneous effects of revascularization. Up-regulated stress and cytoskeletal proteins normalized, while reduced contractile and metabolic proteins persisted. Conclusions Delayed recovery of hibernating myocardium in the absence of scar may reflect persistent reductions in contractile and metabolic proteins. While revascularization appears to stimulate myocyte proliferation, the persistence of small immature myocytes may also contribute to delayed functional recovery.

Panax Quinquefolium Saponins Attenuate Myocardial Dysfunction Induced by Chronic Ischemia

“…This may explain the greater improvement in WT% and SRS% with PQS. Consistent with previous studies [18,29], myocyte nuclear density was increased by PQS. Treatment with PQS attenuated the cellular hypertrophy, indicating that PQS improve oxygen transport across the sarcolemma in the ischemic myocardium [30].…”

Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium

“…This could reflect the time course of these markers prior to tissue harvesting as well as variations in the time over which cells are Ki67 or pHH3 positive with each treatment. Recent studies have demonstrated that physiological stimuli such as revascularization itself can also stimulate cardiac repair and alter these myocyte proliferation indices 45 . Regardless of the proliferative indices measured at a single time point (which reflect a rate of myocyte division at that point in time), the increase in nuclear density and reduction in myocyte size assessed 4-weeks after treatment reflects the cumulative myocyte increase which was the same with icMSCs and icCDCs.…”

Viability testing to guide myocardial revascularisation in patients with heart failure

“…[18,19] In humans, proliferation may stall due to persistent hypoxia or limited energetic substrate. [20,21] Following revascularisation, cardiomyocyte re-differentiation and proliferation has been observed, which may underlie functional recovery [22].…”