Interstitial Fibrosis in HFpEF Attenuates Diastolic Circumferential Strain and the Transcriptional Response to Left Ventricular Pressure Overload

Abstract

Objective We previously demonstrated thattransient repetitive pressure overload (RPO) in swine leads to myocardial interstitial fibrosis and reduced diastolic left ventricular (LV) compliance. While this phenotype is similar to that found in some patients with heart failure with preserved ejection fraction (HFpEF), it occurs in the absence of anatomic LV hypertrophy, persistent hypertension, or comorbidities. The present study was designed to determine if reduced LV diastolic distensibility alters the acute transcriptional response to transient pressure overload. Methods A total of 21 swine were studied. Hemodynamic assessment, echocardiography, and blood sampling were performed before and after a 60 minute intravenous infusion of phenylephrine (PE; 300 μg/min) to elevate LV end-diastolic pressure (EDP) to ~30 mmHg. Myocardial RNA from control animals (n=7) was compared to tissue isolated 24 hours after a single episode of pressure overload (n=6) or after 14 days of RPO (n=8). We assessed LV diastolic strain and compliance via echocardiography and quantified interstitial fibrosis with picrosirius red staining. Genes previously demonstrated to be altered after pressure overload including natriuretic peptides (ANP and BNP), inflammatory mediators (CD68 and CCR2) and pro-fibrotic factors (LOXL2 and Fibronectin) were assessed with quantitative PCR and normalized to β2 microglobulin. Results Transient PE infusion increased LV EDP from 14 ± 1 to 30 ± 1 mmHg and systolic arterial pressure from 120 ± 6 to 205 ± 6 mmHg (both p<0.01). The hemodynamic response to PE was similar during a single episode of pressure overload and after 14 days of RPO. There was concentric LV remodeling (LV mass/EDV: 1.3 ± 0.1 vs. 1.1 ± 0.1 g/mL; p<0.05) without anatomic hypertrophy after RPO (LV mass/body mass: 2.4 ± 0.1 vs. 2.3 ± 0.1 g/kg; p=0.37), yet interstitial fibrosis increased from 6.6 ± 0.7% to 12.9 ± 1.8% (p<0.05) and LV diastolic compliance (∆EDV/∆EDP) decreased from 1.7 ± 0.2 to 0.6 ± 0.2 mL/mmHg (p<0.05). As a result, myocardial diastolic circumferential strain after RPO was markedly reduced in comparison to a single episode of pressure overload in the normal heart (1.5 ± 2.7% after RPO vs. 11.1 ± 3.0% in controls; p<0.05). The reduction in diastolic circumferential strain after RPO markedly attenuated the transcriptional response to acute pressure overload (Figure). In normal myocardium, transient pressure overload upregulated natriuretic peptides (ANP 26-fold and BNP 12-fold; both p<0.01), pro-inflammatory genes (CD68 2.3-fold and CCR2 4-fold; p=0.06), and pro-fibrotic genes (LOXL2 3.4-fold and fibronectin 3.9-fold; p<0.05). In contrast, the reduction in diastolic strain after RPO prevented any increase in gene expression despite a similar magnitude of transient pressure overload. Conclusions These results dissociate the effects of myocardial strain from systolic and end-diastolic pressure on the transcriptional response to LV pressure overload. The dependence of gene expression on diastolic strain rather than LV pressure may explain observations such as the frequent absence of natriuretic peptide elevation in patients with HFpEF.