Abstract 4146115: Contribution of Preload Elevation vs. Ischemia to Pro-Fibrotic Signaling and Interstitial Collagen Deposition in Swine with Chronic Coronary Artery Disease

Introduction: We recently observed that transient elevations in preload are common in swine with multi-vessel coronary artery disease (MV-CAD), presumably due to intermittent demand-induced ischemia of a large perfusion territory. Based on evidence that repetitive preload elevation can lead to fibrosis in the absence of ischemia, we hypothesized that mechanical stretch, rather than ischemia, maybe a key mechanism underlying extracellular matrix (ECM) remodeling in chronic CAD. To test this hypothesis, we compared regional pro-fibrotic gene expression and interstitial collagen in swine with MV-CAD to that observed in swine with single-vessel CAD (SV-CAD) in which the size of the culprit artery perfusion territory is insufficient to cause preload elevation during acute ischemia. Methods: Juvenile swine were instrumented with fixed 1.5 mm stenoses on the left anterior descending and left circumflex (LCx) coronary arteries (MV-CAD; n=6) or the LCx only (SV-CAD; n=6). Three months later, LV tissue was collected from the free wall (ischemic region) and posterior wall (non-ischemic region) to quantify pro-fibrotic gene expression (qPCR) and interstitial collagen (picrosirius red staining) vs. controls (n=11). Results: LCx stenosis severity was similar between MV-CAD and SV-CAD groups (90±4 vs. 82±7%; p=0.4). Pro-fibrotic gene expression was significantly elevated in both ischemic and non-ischemic regions within the MV-CAD group but was generally absent in animals with SV-CAD ( A ). This corresponded with a significant increase in interstitial collagen in ischemic and non-ischemic regions of the LV in animals with MV-CAD ( B ). In contrast, the SV-CAD group did not exhibit increased interstitial collagen in either the ischemic or non-ischemic region of the LV vs. controls. Conclusion: Pro-fibrotic gene expression and interstitial collagen are not altered in swine with chronic LCx stenosis, suggesting that ischemia alone may not be sufficient to elicit ECM remodeling. Conversely, swine with MV-CAD exhibit an increase in pro-fibrotic gene expression and interstitial collagen that is not restricted to the ischemic area of the LV, implicating repetitive preload elevation as a potential mechanism underlying ECM remodeling in CAD.