Left ventricular chamber stiffness and strain determines the myocardial transcriptional response to elevated filling pressure

Transient hypertension precedes sustained hypertension and can arise from reduced aortic compliance with aging. We recently demonstrated that daily hypertension transients in swine rapidly lead to irreversible increases in left ventricular (LV) chamber stiffness without the development of anatomic hypertrophy (LVH). This dissociation was surprising and led us to hypothesize that the transcriptional response to pressure overload was determined by LV diastolic chamber stiffness. Myocardial tissue for RNASeq was obtained 24 h after transient pressure elevation (left ventricular end-diastolic pressure from 12.2 ± 0.8 mmHg to 34.3 ± 2 mmHg and LVSP from 105 ± 3 mmHg to 223 ± 8 mmHg) using phenylephrine. Animals with a single episode [single pressure overload (SPO), n = 6] were compared with those with daily repetitive pressure overload (RPO) for 2 wk (RPO, n = 8). After RPO, LV diastolic chamber stiffness increased fourfold (0.55 ± 0.08 to 2.38 ± 0.50 mmHg/mL/m² after RPO, P < 0.01) and fibrosis increased (normal 5.7 ± 0.2% to 12.9 ± 1.8% after RPO, P < 0.01) without the development of LVH (128 ± 6.6 g/m² vs. 129 ± 3.6 g/m² after RPO, p-ns). There was a robust transcriptional response to SPO, with 5,885 of 12,483 genes (47%) differentially expressed (DEGs). These included potential determinants of chamber stiffness (extracellular matrix, fibrosis, and actin-cytoskeleton), hypertrophy, and inflammation. In contrast, after 2 wk of RPO, the transcriptional response to similar elevations in pressure was markedly attenuated with only 841 DEGs (7%). Our data indicate that LV chamber stiffness is a key determinant of the transcriptional response to pressure overload that attenuates hypertrophic gene expression. This may explain the wide variability of LVH among patients with a similar extent of pressure overload.