Brief Repetitive Pressure Overload Elicits a Fibrosis-Independent Reduction in Left Ventricular Diastolic Compliance in Swine

Abstract

Objective: We have previously shown that swine subjected to repetitive pressure overload (RPO) via daily 2-hr infusions of phenylephrine (PE) develop a reduction in left ventricular (LV) diastolic compliance that coincides with increased interstitial myocardial fibrosis. The objective of the present study was to determine if brief episodes of RPO produce a similar cardiac phenotype. Methods: Swine (n=6) were subjected to a single 30-min PE infusion (300 μg/min) to determine if brief pressure overload causes myocardial injury (circulating cardiac troponin I; cTnI), inflammation (IL-6), and cardiac dysfunction (echocardiography). A separate group of swine (n=5) were subsequently instrumented with an indwelling venous catheter to enable daily 30-min PE infusions for 2 weeks (“Brief RPO”). LV diastolic compliance (ΔLVEDV/ΔLVEDP during PE) and interstitial fibrosis (picrosirius red staining) were compared to values derived from swine subjected to prolonged RPO (2-hr PE/day; n=8) and age-matched controls (n=8). Results: A single episode of brief pressure overload led to an increase in circulating cTnI (from 22±6 ng/L at baseline to 365±12 ng/L 3-hours post-PE) and IL-6 (from 10±2 to 34±4 pg/mL), along with a transient reduction in LV ejection fraction (from 65±2 to 45±5 %, all p<0.05). Brief RPO led to a significant reduction in LV diastolic compliance (ΔLVEDV/ΔLVEDP: 0.59±0.13 mL/mmHg vs. 1.87±0.12 mL/mmHg in controls; p<0.01) that was nearly identical to that observed after prolonged RPO (0.58±0.17 mL/mmHg, p=0.95). Surprisingly, in contrast to prolonged RPO (10.0±1.4% collagen) the brief RPO-induced reduction in LV compliance was not accompanied by an increase in interstitial fibrosis (5.0±0.3 % collagen vs. 5.0±0.3 % collagen in controls, p=0.95). Conclusion: Brief pressure overload initially causes myocardial injury and inflammation, with repetitive exposure leading to a reduction in LV compliance that is similar to that observed following prolonged RPO. However, the brief RPO-induced reduction in LV compliance occurs in the absence of fibrosis, suggesting that mechanisms of repetitive stretch-induced myocardial stiffening may depend on the duration of episodic pressure overload. Supported by funding from the U.S. Department of Veterans Affairs and National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.