Persistent Interstitial Fibrosis and Left Ventricular Stiffening Despite Cessation of Repetitive Pressure Overload in Swine

Background: Swine subjected to brief repetitive pressure overload (RPO) rapidly develop interstitial fibrosis and reduced left ventricular (LV) compliance in the absence of anatomic hypertrophy.Objective: The present study was designed to determine whether these changes reverse after cessation of RPO. Methods: We transiently elevated LV end-diastolic pressure (LVEDP) to ~35 mmHg by increasing afterload with phenylephrine (300 μg/min iv; 2-hours/day). LV compliance and fibrosis were assessed following 2-weeks of RPO as well as 2-weeks (n=6) and 4-weeks (n=6) after cessation of RPO.Results: Chamber dilatation during phenylephrine was markedly attenuated after 2-weeks of RPO (ΔLVEDV: 3{plus/minus}1 vs. 11{plus/minus}1 mL/m2 at the initial study, p<0.01). This reflected reduced LV diastolic compliance (ΔLVEDV/ΔLVEDP: 0.4{plus/minus}0.1 vs. 1.3{plus/minus}0.1 mL/mmHg, p<0.01) and increased interstitial fibrosis (12.9{plus/minus}1.8% vs. 6.6{plus/minus}0.7% in normals, p<0.05). Despite cessation of RPO, reductions in LV diastolic compliance remained unchanged after 2-weeks (ΔLVEDV/ΔLVEDP: 0.6{plus/minus}0.3 mL/mmHg, p=0.63 vs. 2-weeks RPO) and 4-weeks of recovery (ΔLVEDV/ΔLVEDP: 0.7{plus/minus}0.2 mL/mmHg, p=0.54 vs. 2-weeks RPO). There was no reduction in interstitial fibrosis after 2-weeks (16.3{plus/minus}1.1 %) or 4-weeks (14.4{plus/minus}1.6 %) of recovery. The persistent reduction in LV compliance after normalization of hemodynamics continued to attenuate the transcriptional response to acute pressure overload and prevent strain-induced cTnI release and myocardial dysfunction.Conclusion: Once developed, the interstitial fibrosis and reduced LV compliance arising from brief RPO persist despite normalization of hemodynamics. This irreversibility may underlie persistent reductions in LV compliance despite blood pressure control in some patients with heart failure with preserved ejection fraction.