Abstract 4370247: Increased Left Ventricular Chamber Stiffness is Dissociated from Duration Dependent Increases in Interstitial Fibrosis Arising from Transient Hypertension in Swine

Objective: Swine subjected to 2-hour episodes of transient repetitive pressure overload (RPO) develop increased LV chamber stiffness and fibrosis after 2-weeks. These changes persist for at least 1-month after the normalization of blood pressure. We sought to determine whether shorter durations of transient hypertension that approach those encountered in patients could lead to similar elevations in LV stiffness and myocardial fibrosis that might be more rapidly reversible. Methods: Swine were subjected to varying durations of daily phenylephrine (PE) infusion (300-400µg/min) to produce RPO lasting 120-min (n=6), 60-min (n=6) or 30-min (n=6) and compared to 7 normal controls. After 2-weeks of RPO, transient PE infusions were stopped to normalize blood pressure and animals were studied 4-weeks after recovery from RPO. Physiological studies were performed to assess LV diastolic properties in the closed chest propofol sedated state. LV chamber stiffness (ΔLVEDP/ΔLVEDV) was determined using echocardiography and invasive LVEDP measurements at rest and during PE-induced preload elevation. Myocardial interstitial fibrosis was determined by picrosirius red staining and a whole slide pixel classifier analysis. Results: Each duration of RPO produced a similar increase in LV chamber stiffness (Figure A) compared to normal controls (Normal 0.58±0.07, 30-min 1.4±0.16, 60-min 1.17±0.11, 120-min 1.26±.24 mmHg/mL/m 2 , all p<0.05 vs. Normal; 120-min and 60-min p-ns vs. 30-min). There was also no effect of RPO on LV mass index (Normal 125±6.7, 30-min 122±8.7, 60-min 126±4.1, 120-min 129±10.1 g/m 2 ) (Figure B). In contrast, although fibrosis (Figure C) was not increased after 30-min RPO (30-min 4.05±0.22%, p=ns vs Normal), it progressively increased after 60-min (7.46±0.41%, p<0.05 vs 30-min) and 120-min RPO (10.1±1.39%, p<0.01 vs 30-min, p=0.076 vs. 60-min). Individual results showed no correlation between increased LV chamber stiffness and fibrosis (Figure D). Conclusion: We conclude 1.) A cumulative duration of transient pressure overload ranging from 7 hours (30-min RPO) to 28 hours (120-min RPO) is sufficient to produce sustained increases in LV chamber stiffness without the development of LV hypertrophy, 2.) The degree of fibrosis increases as the duration of RPO increases and 3.) Increased LV chamber stiffness from RPO is independent of fibrosis. These data suggest that transient hypertension can elicit a long-lasting effect on LV diastolic properties.